International Journal of Health & Allied Sciences

: 2019  |  Volume : 8  |  Issue : 1  |  Page : 1--24

Molecular mediators, characterization of signaling pathways with descriptions of cellular distinctions in pathophysiology of cardiac hypertrophy and molecular changes underlying a transition to heart failure

Leta Shiferaw Melaku1, Tewodros Desalegn2,  
1 Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Oromia, Ethiopia
2 Department of Public Health, College of Health Sciences, Arsi University, Asella, Oromia, Ethiopia

Correspondence Address:
Mr. Leta Shiferaw Melaku
Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Oromia


The heart is composed of cardiac myocytes, nonmyocytes, and surrounding extracellular matrix. Cardiac hypertrophy (CH) is molecular, cellular, and interstitial changes that manifest clinically as changes in size, shape, and function of the heart in a response to mechanical and neurohormonal stimuli. CH is recognized as an adaptive process to a variety of physiological and pathological conditions. Although adult-onset hypertrophy can ultimately lead to disease, CH is not necessarily maladaptive and can even be beneficial. It enables myocytes to increase their work output, which improves cardiac pump function. The pathophysiology of CH is complex and multifactorial, as it touches on several cellular and molecular systems. Numerous mediators have been found to be involved in its pathogenesis that includes mitogen-activated protein kinases, protein kinase C, insulin-like growth factor-1, phosphoinositide 3-kinase-Akt/protein kinase B, calcineurin-nuclear factor of activated T cell, and mammalian target of rapamycin. CH is usually considered a poor prognostic sign and is associated with nearly all forms of heart failure. Understanding the molecular background of CH is essential to slow down the destined progression to heart failure. CH has been considered as an important risk factor for cardiac morbidity and mortality whose prevalence has increased during the past few decades. This knowledge will allow the identification of novel molecular targets for pharmacological intervention and will assist the future development of therapeutic strategies for managing cardiovascular disorders. This brief review will give a general overview of basic morphology of heart, various molecular signal transduction pathways, the regulators of CH, and molecular changes underlying a transition to heart failure.

How to cite this article:
Melaku LS, Desalegn T. Molecular mediators, characterization of signaling pathways with descriptions of cellular distinctions in pathophysiology of cardiac hypertrophy and molecular changes underlying a transition to heart failure.Int J Health Allied Sci 2019;8:1-24

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Melaku LS, Desalegn T. Molecular mediators, characterization of signaling pathways with descriptions of cellular distinctions in pathophysiology of cardiac hypertrophy and molecular changes underlying a transition to heart failure. Int J Health Allied Sci [serial online] 2019 [cited 2019 Mar 22 ];8:1-24
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The heart is composed of cardiac myocytes, nonmyocytes (e.g., fibroblasts, endothelial cells, mast cells, and vascular smooth muscle cells), and surrounding extracellular matrix (ECM).[1],[2],[3],[4] The cardiomyocyte is cylindrical, with a diameter of about 10–15 μm and a length of about 100 μm [Figure 1].[5] It is striated and has one or two centrally located, nondense, slightly elongated nuclei.[2],[5],[6],[7] Usually, it branches and is connected to its adjacent cardiomyocytes along the longitudinal axis, through the intercalated discs [Figure 1].[6],[7],[8] In fact, the intercalated disc is a synaptic complex with a specific functional mission: to provide proper connection and communication between myocardial cells [Figure 2].[2],[9] The total remaining of sarcolemma (the myocardial cell's membrane) apart from the intercalated disc is called the lateral sarcolemmatic area.[10] A distinctive feature of the lateral sarcolemmatic area, present at the Z-disc level, is the transverse tubular system, or T-system, which allows fast and uniform transmission of the cell membrane's action potential to the muscle fiber [Figure 1].[6],[10] In the T-system, potassium channels and their subunits, minK, are present.[8],[11]{Figure 1}{Figure 2}

In cardiomyocytes length of sarcomere ranges from about 1.6 to 2.2 μm and they are connected serially to form a myofibril.[5],[12] Consequently, the myocardial cell's inner part consists of many fascicles of myofibrils, each of which has a diameter of approximately 1–2 μm.[7],[13] In the two sarcomere ends, Z-discs are located.[7],[12],[13],[14] The thin actin filaments are attached to the Z-discs and extend in the opposite direction from both sides of the Z-disc.[12],[13] Among the actin filaments, there are thick myosin filaments.[10] The thin and thick filaments are the most important elements for the execution of the contraction cycle.[10] A thick myosin filament is surrounded by six actin filaments circularly forming a hexagon.[2],[15] The sarcomere is divided into the following bands (or zones): the A-band is the area where thin and thick filaments overlap; the I-band consists only of thin filaments; and the H-band consists only of thick filaments.[10] The H-band partition is made by the M-line, an area where neighboring thick filaments are laterally connected [Figure 3].[7],[8],[12]{Figure 3}

In mammals, at birth or soon after, it is generally believed that most cardiac myocytes lose their ability to proliferate and growth occurs primarily as a result of an increase in myocyte size.[16],[17],[18],[19] The inability of adult cardiac myocytes to divide has come under some debate.[20],[21],[22] However, the growth of cardiac myocytes is dependent on the initiation of several events in response to an increase in functional load, including activation of signaling pathways, changes in gene expression, increases in the rate of protein synthesis, and the organization of contractile proteins into sarcomeric units [Figure 4].[1],[23],[24]{Figure 4}

Cardiac hypertrophy (CH) is regarded as the myocardial response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress.[25],[26],[27] Macroscopic findings define CH as a thickening of the interventricular wall and/or septum;[28] in the cell, it is characterized by an increment in cardiomyocyte size, mainly left ventricle, with increased protein synthesis and changes in the organization of the sarcomeric structure[29],[30] CH may develop due to either an increase in mechanical stress or an increase in neurohormonal stimulation which could be as a result of pressure and volume overload on the myocardium.[30],[31],[32],[33] Other possible causes include high blood pressure, heart valve disease, weakness of heart muscle, abnormal heartbeat, anemia, thyroid disorders, excessive iron in the body, protein build up in the heart and amyloidosis, which collectively have been noted to reduce adenosine triphosphate (ATP) synthesis in cardiac mitochondria ultimately leading to the development and progression of CH.[27],[34]

 Classification of Cardiac Hypertrophy

CH has been classified as physiological and pathological hypertrophy.[27],[35],[36] Both pathological and physiological cardiac hypertrophies are caused by different stimuli, functionally distinguishable, and are associated with distinct structural and molecular phenotypes [Table 1].[17],[27],[35],[36] Physiological hypertrophy is the normal reversible response which results in increased myocardial muscle mass and pumping ability without morbid effect on cardiac function.[17],[37] It includes normal postnatal growth, pregnancy-induced growth, and exercise-induced CH.[27],[38],[39] At the molecular levels, it seems to be characterized by increased expression of sarcomeric genes, i.e., α-myosin heavy chain (MHC) and cardiac α-actin. This normal growth of heart postnatally or in conditioned athletes enhances cardiac output to meet increased metabolic demands.[39],[40] The pathological hypertrophy is the response of myocardium to pathological stress signals (e.g., neurohormonal activation, aortic stenosis, inflammation, or cardiac).[17] It occurs in response to chronic pressure or volume overload in a disease setting (e.g., hypertension and valvular heart disease), myocardial infarction (MI) or ischemia associated with coronary artery disease, or abnormalities/conditions that lead to cardiomyopathy (e.g., inherited genetic mutations, diabetes).[41],[42],[43] Initially, it may be adaptive to normalize wall stress and to preserve contractile performance but can proceed to decompensation and heart failure.[40] The pathological hypertrophy leads to an increased muscle mass and accumulation of collagen inside the myocardium.[44],[45] This is often associated with impaired myocardial vascularization, unfavorable changes in ECM composition and fibrosis.[17] Notably, at the molecular level, pathological hypertrophy is characterized by the activation of gene expression patterns of the fetal stage.[39],[40] Both physiological and pathological heart growths are associated with an increase in heart size; however, pathological hypertrophy is also generally associated with the loss of myocytes and fibrotic replacement, cardiac dysfunction, and increased risk of heart failure and sudden death.[46],[47],[48] In contrast, physiological growth is associated with normal cardiac structure, normal or improved cardiac function, and is reversible in the instance of exercise- or pregnancy-induced hypertrophy.[49],[50],[51]{Table 1}

From a phenotypic point of view, both pathological and physiological hypertrophies have classically been subdivided as concentric or eccentric.[27],[52] These classifications are based on changes in shape, which is dependent on the initiating stimulus.[35],[36] Concentric hypertrophy refers to an increase in relative wall thickness and cardiac mass, with a small reduction or no change in chamber volume.[27] It is caused by chronic pressure overload and characterized within the cell by the addition of sarcomeres in parallel with the cardiomyocytes "increasing in myocyte length is less than increase in myocyte width." It leads to reduced left ventricular volume and increased wall thickness.[40],[53] Eccentric hypertrophy refers to an increase in cardiac mass with increased chamber volume, i.e., dilated chambers.[52] Relative wall thickness may be normal, decreased, or increased. It occurs due to volume overload and characterized by the addition of sarcomeres in series with the cardiomyocytes "increase in myocyte length is greater than increase in myocyte width."[52] It causes dilatation and thinning of the heart wall.[40],[53] A pathological stimulus causing pressure overload produces an increase in systolic wall stress that results in concentric hypertrophy which is characterized by thick walls and relatively small cavities in the myocardium, whereas, a pathological stimulus causing volume overload produces an increase in diastolic wall stress resulting in eccentric hypertrophy which is characterized by large dilated cavities and relatively thin walls in the myocardium.[35],[36],[54] Clinical studies suggest that eccentric CH induced by pathological stimuli poses a greater risk than concentric CH.[55] Physiological stimuli can also produce concentric or eccentric hypertrophy. Aerobic exercise (also referred to as endurance training, isotonic or dynamic exercise, e.g., long-distance running, swimming) and pregnancy increase venous return to the heart resulting in volume overload and eccentric hypertrophy.[1],[36],[38] Isotonic exercises such as running, walking, cycling, and swimming involve movement of large muscle groups. The intense vasodilatation of the skeletal muscle vasculature produces eccentric hypertrophy by increasing the venous return to the myocardium causing volume overload, characterized by chamber enlargement and a proportional change in wall thickness.[1],[36] This type of eccentric hypertrophy is usually characterized by chamber enlargement and a proportional change in wall thickness, whereas eccentric hypertrophy in settings of disease is generally associated with thinning of the ventricular walls. Strength training (also referred to as isometric or static exercise, e.g., weightlifting, wrestling, and throwing heavy objects) results in reflex and mechanical changes that cause a pressure load on the heart rather than volume load and it modestly increases cardiac output that facilitate the development of concentric hypertrophy without chamber dilation and an increase in peripheral vascular resistance [Figure 5].[1],[36] In pathological hypertrophy, the enlargement of cardiac myocytes along with the formation of new sarcomeres normalizes ventricle wall stress and allows normal cardiovascular function at rest, known as compensated growth.[56],[57] Moreover, function in the hypertrophied heart eventually decompensate ultimately leading to the left ventricle dilation and heart failure, whereas physiological hypertrophy does not decompensate into dilated cardiomyopathy or heart failure [Figure 5].[1],[36],[51],[54] Although CH initially constitutes a compensatory response that transiently normalizes the biomechanical stress and optimizes cardiac pump function, prolonged hypertrophy is a highly important risk factor for the development of heart failure.[46],[58]{Figure 5}

 Molecular Mediators of Cardiac Hypertrophy

Mechanical stress

At the cellular level, cardiomyocyte hypertrophy is characterized by an increase in cell size, enhanced protein synthesis, and heightened organization of the sarcomere.[29],[30] The mechanical stress induced by the physical stretching of adult and neonatal cardiomyocytes is sufficient to induce a phenotypic and genetic hypertrophic response, even in the absence of humoral and neuronal factors [Figure 6].[59] Stress has long been recognized as a biochemical regulator of the activity of many types of cells such as, for example, the skeletal myocytes[60] in which the force generated on the membrane is sufficient to alter some enzyme activities.[61] As a result, several types of molecules have been proposed as candidates to fulfil this role, in particular, the ion channels[62],[63] integrins,[64] and tyrosine kinases.[65] Despite its pathophysiological importance, little is known about how this biomechanical stress is perceived by the cardiomyocyte and how this is translated into prohypertrophic intracellular signals.[30] It is conventionally assumed that, for a mechanosensitive molecule to quantify plasma membrane stress, there should be some interaction between the two. The sarcomeric Z-disc and its associated proteins have been suggested to drive mechanical stress-induced signal transduction, a process referred to as "mechanotransduction."[66],[67],[68] Mouse cardiomyocytes lacking the muscle LIM protein (LIM is itself an acronym resulting from the initials of the first three members of this increasingly growing family of proteins: lin-11, islet-1, mec-3), which is normally present in the Z disc, exhibit a selective absence of the response to mechanical stretch, but respond normally to G protein-coupled receptor agonists; on the other hand, in humans, a MLP gene mutation results in telethonin/T-cap bond breakage, which leads to dilated cardiomyopathy.[68] Frey et al.[69] recently reported a novel family of proteins specific for sarcomeric Z-disc of striated muscle, referred to as calsarcins or myozenins, which are capable of interacting with both telethonin/T-cap and calcineurin, a circumstance that indicates a possible role as a link between the capture of the mechanical stimulus and hypertrophic signaling. Calsarcins were shown to couple the cardiac skeletal apparatus to signaling molecules that can directly influence gene expression.[69] Calsarcins were shown to couple the cardiac skeletal apparatus to signaling molecules that can directly influence gene expression. They do this by binding to the Z-disc myofilament anchor proteins, α-actinin and telethonin, and tethering them to calcineurin, a calcium-dependent phosphatase that was shown to directly induce cardiomyocyte hypertrophy by downstream transcriptional pathways.[69],[70] Calsarcin-1 is the only member of calsarcin family which is expressed in adult heart and slow-twitch skeletal muscle, whereas calsarcin 2 and 3 are expressed in fast twitch muscle.[52]{Figure 6}

Despite our limited knowledge concerning its receptors and transduction pathways, the importance of the mechanical stimulus in triggering the hypertrophic process is supported by a large body of evidence from studies of different types.[33] In addition, it is now accepted that mechanical stress acts as the initial stimulus in the series of events that results in in vivo myocyte growth.[31] This has led to the search for better experimental models that enable us to faithfully mimic the in vivo situation of the cardiomyocyte, resulting in the availability of a considerable number of methodological approaches for the mechanical stimulation of these cells. The changes in the myocardium of a hypertensive patient occur not only in the left ventricle, which is directly exposed to the hemodynamic overload but also in the interventricular septum and right ventricle, as well.[32] On the other hand, the infarcted myocardium presents phenotypic alterations in regions far from the necrosed tissue.[30] This evidence indicates that together with the mechanical component that acts in the myocardial region that is directly subjected to stress; humoral factors intervene, exerting their action more diffusely.[32] There are some humoral factors that can act as a hypertrophic stimulus in the cardiomyocyte, and the consequences of their activation differ. A first group consists of the growth factors (transforming growth factor-beta [TGF-b], fibroblast growth factor [FGF], and insulin-like growth factor [IGF], among others)[71],[72] which, through their action in membrane receptors with tyrosine kinase activity, activate an intracellular second messenger cascade which ultimately leads to a normal growth pattern, characteristic of postnatal myocyte growth (also referred to as eutrophy), and of physiological or adaptive hypertrophic growth.

Humoral stimuli

Humoral stimuli, on the other hand, act on cell surface receptors, triggering downstream second messenger cascades, finally culminating in cellular hypertrophic response and the associated gene expression program [Figure 6].[73] Based on their target receptor, humoral stimuli can be nested under two major groups. The first are targeted by growth factors, such as insulin-like growth factor-1 (IGF-1) and transforming growth factor beta (TGF-β), which act on tyrosine kinase-coupled receptors (RTKs) and are responsible for the eutrophic, as well as adaptive (physiological), myocyte growth.[73] On the other hand, G-protein-coupled receptors (GPCRs)-activating molecules, such as catecholamines, angiotensin II, and endothelin-1, are linked to the ominous progression to heart failure, and hence have been the target of many pharmacological antagonists.[74],[75] This strongly suggests that a cardiomyocyte undergoing physiological hypertrophy uses different signaling pathways than another one undergoing pathological hypertrophy.[30] A good example supporting this notion is the calcineurin-nuclear factor of activated T cells (NFAT) signaling axis, which was shown to activate pathological hypertrophy.[76] Sustained elevation of calcium ions (Ca2+) downstream of GPCR (αq/α11 subclass) is sensed by calmodulin (Cam) and conveyed to calcineurin, an obligate dimer of regulatory and catalytic subunits with phosphatase activity. Once activated, calcineurin tightly binds and dephosphorylates conserved serine residues at the N-terminus of cytoplasmic NFAT transcription factors, permitting their translocation to the nucleus and activation of pathological hypertrophic gene expression.[77] Similarly, activation of the mitogen-activated protein kinases (MAPKs) c-Jun N-terminal kinase (JNK) was also shown to contribute to pathological hypertrophic maladaptive gene expression. On the other hand, physiological hypertrophy, such as that induced by exercise, utilizes a different signaling pathway, mainly through phosphoinositide 3-kinase (PI3K), Akt protein kinase B (PKB), and the mammalian target of rapamycin (mTOR).[77] Studies from genetically modified animal models corroborate this notion, as Akt1–/– mice were shown to be defective in exercise-induced CH.[66] However, one should be careful in interpreting this phenomenon, This is because cellular signaling pathways are highly intricate and interconnected, and pathways activated by either physiological and pathological pathways can converge downstream of different stimuli, as in the case of the MAPK signaling cascade, which can be initiated by GPCRs, RTKs, receptor serine/threonine kinases, and glycoprotein receptors (e.g., gp130), as well as stretching stress [Figure 6].[66]

Transcriptional switch to the fetal gene program

A characteristic feature of pathological CH is the switch to the fetal gene expression profile, including upregulation of cardiac MHC-beta in lieu of the adult predominant alpha isoform (MHC-α), skeletal alpha-actin, and atrial natriuretic factor (ANF) genes.[78] The significance of changes in the fetal genes with regard to their direct effects on cardiac growth and phenotype (e.g., fibrosis) are not completely understood. Although fetal genes are often upregulated in models of pathological hypertrophy, some studies have demonstrated that the fetal gene program can be upregulated in mice without CH.[79],[80] Furthermore, upregulation of some fetal genes may be beneficial. Evidence suggests that atrial natriuretic peptide/B-type natriuretic peptide (ANP/BNP) signaling has antihypertrophic actions within cardiac myocytes.[81] It is also of note that some transgenic models of physiological hypertrophy have been associated with a modest upregulation of fetal genes (e.g., IGF1R[82] and transgenics with increased ERK1/2 activation[83]). Both models were associated with enhanced cardiac function and expression of IGF1R was protective against the induction of interstitial fibrosis in a pressure overload model.[82] In addition, the recently described model of intermittent pressure overload was associated with a pathological phenotype, but not upregulation of the fetal gene program.[84] In addition, cardiomyocytes switch to carbohydrate-dependent energetic machinery instead of fatty acid oxidation, which in turn necessitates alterations in expression levels of metabolic genes.[85] Interestingly, exercise-induced physiological hypertrophy was associated with downregulation of the pathological fetal gene program and suppression of NFAT activity.[86] Cardiac-specific transgenic mice expressing activated forms of calcineurin or NFAT3 developed CH and heart failure.[70] In contrast, calcineurin Ab-deficient mice displayed an impaired hypertrophic response to pathological hypertrophic models (pressure overload, Ang-II infusion, or isoproterenol infusion).[87] Furthermore, when NFAT–luciferase reporter mice were subjected to both physiological stimuli (exercise training, growth hormone–IGF1 infusion) and pathological stimuli (pressure overload, MI), NFAT–luciferase reporter activity was upregulated in both pathological models, but not in the physiological models.[88] In another study, calcineurin signaling was implicated in the induction of both physiological and pathological CHs. Thus, until we have a better understanding of the biological significance of changes in the fetal gene program, it would appear more accurate to categorize models of hypertrophy based on functional and structural parameters.

The role of inflammation

Importantly, inflammation was shown to be a prominent hallmark of ventricular hypertrophy [Figure 6].[89] Interstitial inflammatory cell infiltration involving macrophages, T-lymphocytes, fibrosis, high expression levels of cytokines such as interleukins (IL)-6, IL-1 β, IL-1RA, and tumor necrosis factor-alpha (TNF-α), and activation of inflammatory signaling pathways such as nuclear factor kappa B (NF-kB) are all characteristic hallmarks of a pathologically hypertrophied heart.[90],[91] The pathogenic role inflammation plays is not clearly understood; however, it most probably exacerbates the disease condition. For example, IL-6 was shown to directly induce hypertrophy both in vitro and in vivo.[92],[93] Furthermore, macrophage microRNA-155, induced by pro-inflammatory stimuli, including lipopolysaccharide, TNF-α, and interferon-gamma, promotes CH and failure.[94] In addition, targeting inflammatory cell receptors and mediators was shown to modify the disease process and might preserve cardiac function.[95],[96] The role of inflammatory cells in CH is not to be overlooked. A good example which merits further elaboration is macrophages Mȹ. Mȹ are mononuclear phagocytes widely distributed throughout the body performing important active and regulatory functions in innate and adaptive immunity, as well as a crucial role in tissue remodeling and repair.[97],[98] Two distinct phenotypes of Mȹ can be found in the heart: classically activated pro-inflammatory M1, and alternatively activated anti-inflammatory M2.[98],[99] The former (M1) agitates inflammation in the heart by liberating cytokines and accelerating apoptosis, and contributes to cardiac remodeling.[98],[100],[101] The latter (M2), on the other hand, thwarts inflammation and stimulates cardiac reparative pathways and angiogenesis.[101] A strong link between Mȹ and hypertrophy was established; however, studies have shown that Mȹ depletion aggravates cardiac dysfunction on hypertrophy, suggesting a crucial, yet to be understood role in both disease process and outcome.[98] Taken together, inflammation is an attractive target for studying disease progression and developing new therapeutic interventions.[96],[102]

The role of redox signaling

The role of oxidative stress was shown to be strongly involved in the pathogenesis of ventricular hypertrophy. Reactive oxygen species (ROS) were shown to activate a plethora of signaling pathways implicated in hypertrophic growth and remodeling, including tyrosine kinases, protein kinase C (PKC), and MAPK, among others.[103],[104] Furthermore, ROS were shown to mediate angiotensin II, as well as norepinephrine-induced hypertrophy downstream of GPCR.[105],[106] Anti-oxidant treatment was shown to abolish TNF-α-induced hypertrophy via NF-kB, suggesting an important role of redox signaling in inflammation-induced hypertrophy.[107] Moreover, ROS contribute to contractile dysfunction by direct modification of proteins central to the excitation-contraction coupling (e.g., the Ryanodine receptor).[108] Importantly, ROS are involved in the fibrotic remodeling of the heart due to their interaction with ECM and their activation of matrix metalloproteinase by posttranslational modifications.[109] Finally, ROS can contribute to the loss of myocardial mass upon cardiac remodeling by inducing cardiomyocyte apoptosis [Figure 6].[103]

 Signaling Mechanisms Involved in Cardiac Hypertrophy

Calcineurin/nuclear factor of activated T-cells

The calcineurin-NFAT pathway is one of the first signaling pathways that provide molecular insight about how extracellular signals travel from the cell membrane into the nucleus. Calcineurin is a calmodulin-dependent phosphatase that dephosphorylates transcription factors known as NFAT (nuclear factor of activated T cells).[52] Calcineurin is a heterodimer composed of two distinct subunits, designated calcineurin A (58-59 kDa subunit) which contains the catalytic site of the enzyme, and a small 19 kDa calcineurin B subunit which contains the Ca2+ binding domain. Furthermore till date, five genes encoding NFAT complexes have been identified and designated as NFATc1 (NFATc or NFAT2), NFATc2 (NFATp or NFAT1), NFATc3 (NFAT4 or NFATx), NFATc4 (NFAT3), and NFAT5. NFATc members transactivate target genes by interacting with other transcription factors such as c-myc, activator protein-1 (AP-1) and GATA-4.[110],[111] Furthermore, it acts as a transporter between cytoplasmic and nuclear components under the influence of Ca2+ signal [Figure 7].[112] The mechanical and neurohormonal stimuli stimulate Ca2+-calmodulin binding which regulates the dephosphorylation of NFAT using calcineurin[113] which in turn activates the transcriptional factors such as GATA-4 and thus, lead to hypertrophy.[112] Cyclosporine A (CsA, which inhibits calcineurin) prevented the hypertrophic growth response in cultured cardiomyocytes in response to humoral factors such as Ang-II and PE and thus, calcineurin has also been identified as the cellular target of immunosuppressive agents such as CsA[113],[114] Furthermore, NFATc4 transgenic mice demonstrated hypertrophic myopathy associated with re-expression of fetal genes. CsA was unable to prevent the morphological pathology of NFATc4 transgenic animals, which expresses a calcineurin-dependent activation of the transcriptional factors.[115],[116] Furthermore in numerous rodent-based studies, pharmacological calcineurin inhibition attenuated agonist as well as pressure overload-induced hypertrophy.[117],[118] A more specific approach to inhibit calcineurin was recently made possible by the discovery of endogenous calcineurin modulators such as AKAP79, Cabin/Cain, DSCR/MCIP, and calsarcin. Transgene-mediated overexpression of the calcineurin inhibitory domains of Cain or AKAP79 inhibited calcineurin activity, thereby attenuating both pressure overload and isoproterenol-induced CH.[119],[120] Furthermore, a family of proteins known as MCIP (i.e., myocyte enriched calcineurin-interacting protein family), are capable of binding to and inhibiting catalytic A subunit of calcineurin.[121],[122] This antihypertrophic role of MCIP in heart was shown by animal studies in which overexpression of MCIP-1 inhibited CH, re-induction of fetal gene expression and progression to dilated cardiomyopathy in MCIP-1/calcineurin double transgenic mice. A new family of calcineurin-interacting proteins, calsarcins[29] have been proposed to be critical for hypertrophic calcineurin/NFAT pathway. Calsarcin-1 is the only member of calsarcin family which is expressed in adult heart and slow twitches skeletal muscle, whereas calsarcin 2 and 3 are expressed in fast twitch muscle. Several studies in animal models suggests that calsarcin-1 derogates calcineurin-mediated hypertrophy in vivo as calsarcin-1 deficient mice displayed exaggerated hypertrophic response to pressure overload compared to control animals.[68] Furthermore, heart-specific overexpression of calcineurin in calsarcin-1 deficient mice induced massive cardiac enlargement that exceeded hypertrophy induced by the calcineurin transgene alone. These findings suggest an important role of calsarcin-1 in modulating calcineurin signaling and CH.{Figure 7}

Cyclic guanosine monophosphate/protein kinase G-1

The cyclic GMP (cGMP)/PKG-1 signaling pathway has recently emerged as another promising target for antihypertrophic interventions.[52] cGMP is the second messenger for membrane-bound guanylate cyclase receptors and for ANP, BNP as well as nitric oxide (NO) principle receptors.[123],[124] It has been shown that ANP and BNP directly inhibit CH. Furthermore, the messenger molecule NO-stimulated cGMP formation via activation of guanylyl cyclase and demonstrated antihypertrophic effect.[124] One of the major downstream effectors of cGMP signaling in cardiomyocytes is cGMP-dependent protein kinase-I.[125] It has been proved that cGMP-induced PKG-1 activation reduces NFAT nuclear translocation and its association with transcription factors[125],[126] and thus plays a major role in inhibition of CH [Figure 7].

Phosphoinositide 3-kinase/Akt pathway

PI3K activation occurs downstream to stimulation of tyrosine kinase receptors such as IGF, FGF, TGF as well as G protein-coupled receptors (GPCRs).[127],[128] One of the principal targets of PI3K signaling is the serine/threonine kinase Akt, also known as PKB, which on activation via PI3K binding translocates to the membrane.[52] Oudit et al. demonstrated that PI3Kγ is critical for the induction of myocardial hypertrophy, interstitial fibrosis and cardiac dysfunction in response to β-adrenergic stimulation.[129] This link between β-adrenergic signaling and PI3K/Akt pathway could therefore represent a major promising target for the treatment of transition from CH to heart failure. Furthermore, PI3K/Akt signaling induced hypertrophy is mediated by two direct target proteins, i.e., mTOR (mammalian target of Rapamycin) and glycogen synthase kinase 3 β. The phosphoinositide 3-kinase (PI3K)-Akt signaling pathway is essential in the induction of physiological CH and PKCβ2 has been implicated in the development of pathological CH and heart failure.[52] Recently, study was conducted to demonstrate the association between these two pathways in which the potential interaction between PI3K and PKCβ2 pathways was observed by crossing transgenic mice with cardiac-specific expression of PKCβ2, constitutively active PI3K and dominant negative PI3K. This study suggested that PI3K may act as an upstream modulator of PKCβ2 and this upstream modulation by PI3K may rescue the pathologic cardiac dysfunction induced by overexpression of PKCβ2.[72],[130] When IGF-1, insulin and other growth factors bind to their membrane tyrosine kinase receptors, a 110 kDa lipid kinase, PI3K subgroup Iα (or P110α) is activated and phosphorylates the membrane phospholipid phosphotidyl inositol 4, 5-biphosphate (PIP2).[131] This leads to recruitment of the protein kinase Akt (or PKB) and its activator, 3-phosphoinositide-dependent protein kinase-1 (PDK-1) to the cell membrane. This enforced co-localization of Akt and PDK-1 causes the latter to phosphorylate and activate the former thus, inducing CH. Mc Mullen et al. have discovered the role of P110α isoform of PI3K in transduction of a biochemical pathway of exercise-induced hypertrophy by using transgenic mice expressing a dominant negative PI3K (P110α).[71],[132] Furthermore, exercise causes physiological hypertrophy in mice through activation of the p110α isoform.[80] By contrast, transgenic mice in which p110α is inhibited specifically in the heart (dn PI3Kα mice) do not respond to exercise but show both hypertrophy and cardiac dysfunction in respond to hypertensive pressure overload.[52] Moreover, short-term cardiac-specific inducible overexpression of Akt-1 leads to a compensated state of hypertrophy with preserved contractility. In contrast, long-term overexpression of an activated Akt-1 gene induces contractile dysfunction and dilated cardiomyopathy [Figure 7].[127]

Isoforms of Akt

There are three isoforms of Akt in mammals: Akt1, Akt2, and Akt3. Akt1 and Akt2 are expressed in the heart[133],[134],[135] whereas Akt3 is expressed primarily in brain where it regulates growth[135],[136] Studies in Akt1−/− mice[133],[137],[138],[139] and mice with cardiac overexpression of Akt1[139] suggest that this isoform mainly functions to regulate growth[133],[137],[138] Akt1−/− mice has impaired fetal and postnatal growth[133] but normal glucose tolerance and insulin responses.[133] Mice with constitutively active cardiac Akt1 develop left ventricular hypertrophy (LVH),[139] while Akt1−/− mice are resistant to swim training-induced CH.[140] In addition, isolated myocytes from Akt1−/− mice are resistant to IGF-1-stimulated protein synthesis, suggesting that PI3K-Akt pathways is key for normal heart growth.[141] Akt2−/− mice also exhibit growth retardation but also have severe diabetic symptoms such as insulin resistance, hyperglycemia, hyperinsulemia, and glucose intolerance.[134],[142] On a systemic basis, the Akt2−/− mouse has a more severe phenotype, with both retarded growth and severe symptoms of diabetes[134],[142] while that of the Akt1−/− is mainly isolated to growth.[133]

Myocyte enhancer factor 2/histone deacetylases

Transcriptional factor myocyte enhancer factor 2 (MEF2) integrates Ca2+/Calmodulin dependent signaling pathway and is a common downstream target of various hypertrophic stimuli in heart in the context of myocardial hypertrophy.[118] MEF2 is regulated by a plethora of signaling pathway including MAPKs, calcineurin[143] and its transcriptional activity is enhanced by interaction with other transcription factors such as GATA4 and NFAT.[144] Recent studies demonstrated that MEF2 activity is controlled by a direct association with histone deacetylase (HDAC).[145] There are more than a dozen individual HDAC enzymes which can be divided into three main classes – class I HDACs (HDACs 1, 2, 3, and 8), class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) and class III HADCs.[52] HDACs deacetylate nucleosomal histones, thereby promoting chromatin condensation and transcriptional repression via binding to specific transcriptional factors such as MEF2.[143] HDACs have been shown to be important endpoint targets of cell-signaling pathways involved in the induction of altered gene expression in CH and ischemia/reperfusion injury [Figure 7].

G-protein coupled receptors: Gq/g11 signaling

Myocardial GPCRs represent a group of seven transmembrane spanning domain receptors, which play an important role in the regulation of acute hemodynamic and chronic myocardial effects within the cardiovascular system.[113],[146] There are two forms of signal transducing G proteins: the small G proteins and the heterodimeric G proteins. These G proteins share a common characteristic that they exist in two inter-convertible conformational states, i.e., an inactive guanosine diphosphate bound state and an active guanosine triphosphate (GTP) bound state.[147] All heteromeric G-proteins consists of subunits Gα and Gγ, which dissociate on receptor activation and independently activate intracellular signaling pathways. Like all GPCRs, adrenergic receptors couple to heterodimeric G-proteins which consist of Gα and Gγ subunits.[52] β-adrenergic agonists couple to Gαs subunit and induce adenylyl cyclase activation resulting in accumulation of cAMP and consequently activation of protein kinase A (PKA). PKA phosphorylates several proteins involved in cardiac contraction, including L-type calcium channels, troponin and phospholamban, thus resulting in increased force of contraction.[148] Furthermore, the activation of GPCRs stimulates activation of membrane-bound Gq and functionally similar G11 protein which activates phospholipase C, resulting in hydrolysis of phosphotidylinositol 4, 5-bisphosphate (PIP2). The products of this reaction are inositol 1, 4, 5-triphosphate (IP3), and diacylglycerol (DAG). IP3 mobilizes Ca2+ from intracellular organelle depots, thus increasing intracellular Ca2+ level[149] and DAG activates PKC which is an important step in the development of concentric hypertrophy. Indeed, inhibition of PKC abrogates GPCR-mediated hypertrophy in mice.[150] Various small G-proteins such as Ras, Rho, and Rac are also activated by a variety of Gq/G11 linked agonists, like Ang-II, Et-1, and PE, each of which is sufficient to induce CH.[151],[152] The sustained increase in Ca2+ mediated by IP3 is also responsible for the activation of small GTP binding proteins. Ras-signaling is mediated by potent pro-hypertrophic downstream effectors, including c-Raf,[153] MAPK kinase kinase of the ERK cascade,[154] and the calcineurin-NFAT pathway.[151],[155] Actually, Rho, Ras and cdc42 subfamilies of small G-proteins have been shown to regulate the cytoskeleton organization of cardiomyocytes[156] as well as have role in modulation of cardiac growth via augmentation of hypertrophic gene expression. Rho activates several protein kinases, in particular Rho-associated kinase and facilitates GATA4 transcriptional activity to provoke hypertrophy in rat cardiomyocytes [Figure 6].[157]In vitro studies have also shown that activation of Gαq coupled receptors is responsible for induction of hypertrophy.[158] Gq/G11 signaling is required for pressure overload hypertrophy[159] as well as to provoke hypertrophy in the absence of hemodynamic stress. Thus, Gq signaling seems to be particularly involved in maladaptive cardiac growth.

Mitogen activated protein kinases pathways

MAPK cascade is highly conserved signal transduction pathway which couples various extracellular signals to a range of intracellular responses including cell differentiation, cell movement, cell division, and cell death.[149] They phosphorylate-specific serine and threonine residues of target protein substrates and regulate cellular activities.[160] In MAPK signaling cascade, phosphorylation of MAP kinase kinase kinase (MAPKKK) activates MAP kinase kinase (MAPKK). The activated form of MAPKK undergoes phosphorylation and activates MAPK.[52] Several members of MAPK family have been isolated which includes extracellular signal receptor-regulated kinase (ERKs), cjun NH2-terminal Kinase (JNKs) and p38 MAPK. p38 MAPK and JNKs are well characterized and have been reported to be important for the induction of hypertrophic responses including specific gene expression and increase in protein synthesis,[161],[162] while the ERKs are particularly implicated in growth-associated responses.[163] The major upstream activators of ERK1 and 2 are two MAPK kinases (MAPKKs), MEK1 and MEK2, which directly phosphorylate the dual site in ERK1 and ERK2. Directly upstream of MEK1 and 2 in the MAPK-signaling cascade are the MAPKK kinase (MAPKKK), Raf-1, A-Raf, B-Raf, and MEKK1-3.[164] The c-jun NH2-terminal Kinases (JNKs) and p38 kinases function as specific transducers of stress response, thus they are also categorized as stress-activated protein kinases. JNK activity is specifically upregulated in response to pressure overload, while p38 activity is markedly induced in heart subjected to volume overload.[162] The exposure of cardiac myocytes to stress or GPCR agonists leads to activation of small G proteins such as Ras, Raf which further activates MAPK signaling pathway.[165] Moreover, MAPK is also activated by other kinases such as apoptosis stimulated kinase (ASK1), TGF-β activated kinase (TAK1), and myosin light chain kinase (MLCK3).[166] Furthermore, MAPK is responsible for activation of activator protein-1 (AP-1) transcription factor[167] which comprises c-jun, members of c-fos and family of activation transcription factor-2 (ATF-2).[166],[167] Moreover, AP-1 is an important trans-activator of number of stress-responsive genes including genes for IL-1, IL-2, TNF, and c-jun.[168],[169] Furthermore, p38 MAPK directly phosphorylates ATF-2 and MEF2[170],[171] which activate numerous transcriptional factors and thus, regulate hypertrophic gene expression.[170],[172]

Interleukin-6 family of cytokines and janus associated kinase-stat pathway

Along with adrenergic agonists, cytokines play a major role in induction of hypertrophy. The main hypertrophic cytokines include almost all the members of IL-6 family and include IL-6 itself, leukemia-inhibitory factor (LIF), and cardiotrophin-1 (CT-1).[52] All IL-6 cytokines utilize a common receptor unit glycoprotein 130 (gp130) in combination with ligand-specific receptors and mediate their effects by janus associated kinase/signal transducers and activators of transcription (JAK/STAT), MAPK, and PI3K pathways.[173] The JAK/STAT signaling pathway plays a central role in cardiac pathophysiology.[154] The JAK/STAT pathway involves activation via receptors associated with cytoplasmic JAKs, which have two symmetrical kinases like domains and are thus named after the two-headed mythical Roman God Janus.[174] On activation, the JAKs phosphorylate the cytosolic "signal transducers and activators of transcription" proteins, which lead to their dimerization and translocation to the nucleus where they activate transcription of a variety of genes. A range of different JAKs and STATs exists and using different combinations ensures the specificity of signaling in response to various cytokines. Mammals have four members of JAK family (JAK 1-3 and tyrosine kinase 2), and seven members of the STAT family (STAT 1-4, STAT 5a, STAT 5b, and STAT 6), which are all expressed in cardiac tissue.[175] The STAT factors can function both as modulators of cytokine signaling and as sensors responding to cellular stress which is proved by the fact that activation of STAT occurs also through receptor families such as tyrosine kinase receptors and G-protein coupled receptors, for example, AT-II receptors.[176] JAK-STAT signaling has been implicated in pressure overload-induced CH and remodeling, ischemic preconditioning and ischemia/reperfusion-induced cardiac dysfunction. Furthermore, the JAK-STAT pathway has an important role in cardiomyocyte cytokine signaling.[177] In addition, stress-induced activation of matrix metalloproteinases (MMPs) is mediated by Ang-II activation via the JAK/STAT pathway.[178] Activation of specific STAT proteins constitutes the primary signaling event in the development of CH. In cardiomyocytes, CT-1 induces the activity of several signaling mediators such as ERK1/2, p38 MAPK, STAT3, PI3K/Akt, and NF-κβ. CT-1 signals through the heterodimeric LIF/gp130 receptor and thus it is responsible for the hypertrophic response.[179] Interestingly, in patients with hypertensive heart failure, augmented CT-1 expression is accompanied by downregulation of gp130. It suggests a compensatory mechanism which may control IL-6 family cytokine-mediated hypertrophy.[180],[181] Ang-II treatment induces CT-1 and LIF release from cardiac fibroblasts, while pharmacological inhibition of Ang-II blocks CT-1 and LIF-mediated hypertrophy[182],[183] LIF and CT-1 also leads to rapid tyrosine phosphorylation of gp130, JAK1 (janus activated kinase), STAT1, STAT3 and ERK 1, 2 and 5.[184],[185] Moreover, inhibition of STAT3 in cardiac myocytes has been proved to block LIF-mediated hypertrophy.[185] Despite similar structural organization, STAT 1 and 3 have opposing effects on myocardium with STAT 1 exhibiting pro-apoptotic effects while STAT 3 is able to protect cardiomyocytes from apoptosis after ischemia/reperfusion.[186] Studies have also shown that STAT 5A and STAT 6 are activated during ischemia, whereas activation of STAT3 and STAT5A occurs in myocardial hypertrophy. The JAK/STAT pathway induced by IL-6 family of cytokines is one of the stress/stretch-activated signaling pathway and may contribute significantly to the pathogenesis of CH [Figure 7].[186]

Sodium hydrogen exchanger

The activity of cardiac Na+/H+ exchanger (NHE) increases in cardiomyocytes subjected to mechanical stress as well as in several in vivo models of CH such as pressure overloads induced CH.[187] Enhanced NHE activity reduces the transmembrane Na+ gradient, which leads to increased intracellular Ca2+ levels via the Na+–Ca2+ exchanger. Increased Ca2+ concentration triggers cardiomyocyte hypertrophy via numerous pathways including Ca2+/ Cam (calmodulin), calcineurin and MAPK-dependent pathways.[187] Moreover, NHE activation increases intracellular pH (cytoplasmic alkalization) which is known to stimulate expression of hypertrophic marker genes and increase protein synthesis. Takano et al. have shown that HOE-694 (3-methylsulphonyl-4-piperidinobenzoyl, guanidine hydrochloride), a specific inhibitor of NHE significantly attenuated stretch-induced activation of ERK pathway and protein synthesis stimulation in cultured cardiomyocytes.[188] Furthermore, mechanical stress-induced activation of the MAPK pathway was partially blocked with NH4Cl (cytoplasmic acidification) which suggests that cytoplasmic alkalization could be a crucial step to activate the ERK pathway in mechanical stress-induced CH in cardiomyocytes.[52] Thus, NHE may play a role in inducing CH.[188]

Renin angiotensin system

The renin-angiotensin system (RAS) is integrally involved in cardiovascular and renal homeostasis.[189] The principle mediator of physiological actions of RAS is Ang-II which directly modulates cardiac functions such as myocardial contractility, metabolism, and hypertrophic growth.[52] Ang-II has also been suggested as an important hormonal mediator of CH[190] as it has a role in stimulating protein synthesis, total RNA and mRNA levels in cardiomyocytes.[191] It is one of the growing numbers of peptide hormones that has been implicated in regulation of cellular growth and hypertrophy.[190] Moreover, AT-I and AT-II receptor expressions are upregulated in response to hypertrophic stimuli[191] which may contribute to the growth of heart and hypertrophy of cardiac fibroblasts. Recent studies have shown that cardiomyocytes can produce Ang-II when subjected to stretching in vitro.[192] Once synthesized, Ang-II binds to AT-1 receptors, thus inducing activation of Gαq and GαI molecules; these, in turn, activate PKCs and Ras which are responsible for activation of MAPK cascade. Activation of AT-I/II receptors in cardiomyocytes may play a critical role in Ang-II-induced gene expression and thus may have a critical role in hypertrophy.[189],[191]

Polypeptide growth factors

Recent studies, both in vivo and in vitro suggest that myocardium is the target of selected growth factors[193] which may play an important role in both normal and abnormal growth of the heart.[194] The multifunctional polypeptide growth factors such as TGF, IGF, and FGF have been implicated in signaling process in cardiomyocytes which shows their critical role in regulation of myocardial growth and differentiation.[195],[196] IGF-1 and IGF-2 promote cellular proliferation and/or differentiation through binding to a specific heterotetrameric receptor with intrinsic tyrosine kinase activity.[196] The activated IGF receptor phosphorylates the insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) leading to signal transduction and Ras activation.[52] The regulatory subunit of PI3K interacts with IRS-1, resulting in PI3K activation[197] which further leads to Akt (protein kinase B) activation. A recent study reported that overexpression of the local form of IGF-1 in hearts of transgenic mice was sufficient to induce hypertrophy.[198] While FGF-2 and TGF-β each bind to separate membrane receptors that have intracellular tyrosine kinase activity (FGF) or serine-threonine kinase activity (TGF-β) to elicit further signaling. FGF-2 and its receptor signal elicit myocyte hypertrophy through the activation of MAPK cascade. TGF-β may also play a role in CH as it induces collagen mRNA expression resulting in deposition of collagen proteins by cardiac fibroblasts. Furthermore, it induces skeletal re-expression of genes of fetal isoforms of β-MHC and skeletal α-actin in cardiomyocytes. Moreover, downstream of TGF-β receptor leads to TGF-β activated kinase (TAK1) signaling which can directly activate MAPKK factors, thus leading to JNK and/or p38 activation.[199] TGF-β1 elicits its biological response through serine/threonine kinase receptors such as TβR1 and TβR2 to form heterodimeric complex with TβR1, which further activates serine/threonine kinase that causes phosphorylation of Smad3. The phosphorylated form of Smad3 forms heterooligomer with Smad4 and this complex moves to nucleus and binds with activating transcription factor-2 (ATF-2) to enhance its transcription activity, which is responsible for overexpression of hypertrophic genes.[200] Various hypertrophic stimuli such as Ang-II, NE and mechanical stretch of the ventricular wall are associated with increased secretion of growth factors, increased protein synthesis and activation of a number of hypertrophic markers.[201],[202] Moreover, it may also lead to activation of stretch-sensitive channels[203] which allow the passage of physiological cations such as Na+, K+, and Ca2+.[204] Together, these results implicate the role of growth factors such as IGF, TGF, and FGF in induction of CH followed by increased deposition of ECM proteins by fibroblast [Figure 7].[205]

Atrial natriuretic peptide

ANP is a 28 amino acid peptide secreted by atrial myocytes which causes increase in atrial pressure and acute volume overload and leads to natriuresis and diuresis.[206] The role of various hormones is potentially useful in the treatment of cardiovascular and salt retention diseases such as essential hypertension, congestive heart failure and CH. Being a potent vasodilator and natriuretic agent, ANP is abundantly re-expressed in ventricles subjected to overload to reduce wall stress.[207] Variety of hypertrophic stimuli such as hormonal/mechanical stretch induce ANF gene in ventricular cell and is therefore, a useful genetic marker as well as used as a marker for embryonic gene program in CH.[208] PKC activates c-fos and c-jun genes which further activates ANF gene expression which has also been proven in several experimentally and pathologically induced models of CH.[167] This association between hypertrophy and ventricular ANF gene expression suggests the role of ANF in modulating the development of ventricular hypertrophy.[52]

Nitric oxide

NO is synthesized from L-arginine by a family of NO synthase (NOS) enzymes present in a variety of cells, platelets, neurons, and macrophages.[209] NO is involved in the regulation of blood pressure, platelet function, neurotransmission, and host defense. Within vasculature, continuous synthesis of NO by endothelium exerts a background of vasodilator influence on arterial and arteriolar tone.[52] Inhibition of NO synthesis causes vasoconstriction, increases blood pressure and platelet adhesion to the endothelium. Recent studies indicate the involvement of NO mechanisms in various CVS disorders including hypertension, hypercholesterolemia, diabetes, atherosclerosis, and vascular and CH.[210] Recent studies suggest that decreased synthesis of NO may contribute to development of ventricular hypertrophy and hypertension as it has been shown that endogenous NO inhibits renin release.[211] Moreover, NO-induced vasodilatation inhibits proliferation of vascular smooth muscle cells by a cGMP-mediated process.[212] Furthermore, NO has been reported to inhibit mitogen release from stimulated platelets.[213] In the light of these, it is proposed that NO mechanisms may contribute significantly to the pathogenesis of CH.

Tumor necrosis factor

Development of CH and dilated cardiomyopathy in transgenic mice with selectively over-expressed TNF-α implicates a detrimental role of this cytokine in the heart. Moreover, novel strategies targeting downstream signaling pathways of TNF-α have recently emerged. In this regard, the NF-κβ was activated in mice with cardiac-specific activation of TNF-α and this activation was mediated via TNF-α receptors. Thus, NF-κβ seems to be an important mediator of detrimental effects of TNF-α signaling in the heart. Furthermore, evidence indicates that constitutive expression of TNF-α is in addition localized in cardiac mast cells. Mast cell stimulation activates TNF-α/NF-κβ/IL-6 cascades to induce CH.[52],[214] TNF-α also induces the activation of p38 MAPK, which further activates NF-κβ and various hypertrophic genes to cause CH and heart dysfunction.[215] TNF-α and NF-κβ have been shown to be activated in failing hearts of various etiologies, implicating a role of this transcription factor in the pathophysiology of human heart failure.[216]

Peroxisome proliferator-activated receptor

Energy generation in adult myocardium depends largely on mitochondrial oxidation of long chain fatty acids. CH is associated with suppression of fatty acid oxidation and metabolic reversion of the heart to increased glucose utilization, which is characteristic of fetal heart.[53],[217] This metabolic shift could be viewed as an adaptive response, because it decreases oxygen consumption per mole of ATP generated. However, it leads to certain maladaptive features including increased lipid accumulation in the heart due to impaired oxidation of fatty acids, lactic acid accumulation, and diminished maximal ATP generation from glycolysis.[52] The genes involved in fatty acid oxidation are regulated by the PPAR family of transcription factors. The three PPAR isoforms α, β/δ, and γ belong to a superfamily of nuclear hormone receptors of the heart and are activated by diverse ligands, including unsaturated fatty acids and isoforms of specific drugs, such as fibrates (PPARα) and antidiabetic drugs of thiazolidinediones class (PPARγ).[218] These latter agents have been shown to attenuate angiotensin-II induced hypertrophic gene-expression, as well as increase in cardiomyocyte size in vitro.[217] PPARα, the predominant PPAR isoform in heart, has been implicated in hypertrophic signaling. In addition, PPARs are the target of several mediators which have been implicated in hypertrophic signaling, including PKA, MAPKs, NFAT, and NF-κβ which shows its critical role in hypertrophy.[188] Cardiac gene expression and myocyte growth can, therefore, be activated by ligand binding to PPARs, specifically PPARα and PPARβ/δ.[219],[220],[221],[222],[223],[224] These transcription factors control gene expression by forming a heterodimer with the retinoid X receptors (RXR) and then binding to specific PPAR response elements (PPRE) located within promoter regions of many genes encoding metabolic enzymes.[219] In addition, the PPAR/RXR complex requires the cofactor PPARγ coactivator-1α(PGC-1α).[222] Once bound to the PPRE, the PPAR/RXR/PGC-1 complex increases the rate of transcription of fatty acid oxidation genes.[221],[223],[225],[226] The activity of PPAR/RXR heterodimers is increased by fatty acids and eicosanoids. Thus, PPAR/RXR heterodimers act as lipid sensors in the cell, increasing the capacity for fatty acid catabolism in response to a greater cell exposure to lipid.[222] While the expression of PPARα and PPARβ/δ[221] are high in the heart, PPARγ mRNA is very low and does not appear to play a direct role in regulating fatty acid oxidation.[221],[227]

Effects of adipokines

Since the discovery of leptin over 10 years ago,[228] there has been a great deal of interest in the role of adipose tissue as an endocrine organ, and the effects of adipokines (e.g., leptin, adiponectin, resistin, ghrelin, and visfatin) on eating behavior, substrate metabolism, and cardiac growth and function.[229] At present, relatively little is known about how diet effects the secretion of these peptides or about their sites of production (visceral vs. subcutaneous adipose) and the effects on the heart and vascular system[230],[231],[232],[233] The most studied adipokines are leptin and adiponectin, which both have effects on cardiac growth and metabolism.[229]


Leptin has been implicated as a potential mediator of LVH, primarily due to initial observations that it may increase sympathetic vasoconstrictor tone and increase arterial blood pressure.[234],[235] However, the direct role that leptin plays in vivo in triggering LVH remains unclear. Leptin normally acts to trigger satiety and reduce food intake[228],[236] and is increased ∼4-fold in obese normotensive people compared to lean individuals.[237] Treatment of isolated perfused hearts with leptin increases fatty acid oxidation and reduces cardiac triglyceride stores.[238] In skeletal muscle, leptin stimulates AMP-activated protein kinase (AMPK) and inhibits acetyl-CoA carboxylase (ACC), which increases fatty acid oxidation, presumably due to lower malonyl-CoA levels.[239],[240] However, this effect was not observed in the isolated heart.[238] Interestingly, leptin activation of fatty acid oxidation is greater in innervated skeletal muscle than in denervated muscle, suggesting the possibility that the hypothalamic effects of leptin are mediated through the discharge of peripheral nerves.[239],[240] A strong positive correlation has been observed between fasting plasma leptin levels and increased LV wall thickness independent of blood pressure in a study comparing hypertensive and normotensive male patients.[241] The concept that leptin acts as a direct stimulant for cardiomyocyte growth is supported by studies showing an increase in cell size and protein synthesis in neonatal cardiomyocytes.[242],[243],[244] The mechanism and in vivo implications for these effects are unclear.[229]

Studies in isolated rat myocytes have demonstrated that leptin treatment results in increased protein synthesis and hypertrophy, and that pre-treatment of these cells with a leptin receptor antibody attenuates these hypertrophic effects.[243],[244],[245],[246],[247] In addition, these studies have demonstrated that the leptin-induced ERK1/2 activation was attenuated by Rho protein signaling inhibition, suggesting a possible role for these proteins in leptin-mediated hypertrophy.[229] On the other hand, it has been suggested that diet-induced hyperleptinemia resulting from overnutrition confers differential metabolic effects than obesity-induced hyperleptinemia, which may provide an explanation for hyperleptinemia preventing lipid-induced cardiac dysfunction.[248] The CH and increase in cardiomyocyte apoptosis that is observed in the obese leptin-deficient (ob/ob) mouse is reversed by long-term leptin infusion.[249],[250] Recent interest has focused on the ciliary neurotrophic factor (CNTF), which has receptors on cardiomyocytes that closely resemble those for leptin.[251] Activation of the CNTF signaling pathway regresses LVH in leptin-deficient mice,[252] however the mechanism for this effect is not clear. Studies demonstrated that treatment with CNTF activates AMPK and inhibits ACC, increases fatty acid oxidation, and lowers tissue triglyceride and ceramide content in skeletal muscle, presumably due to lower malonyl-CoA levels.[253],[254] These observations are similar to the effects attributed to leptin treatment in skeletal muscle;[239] however, this mechanism has not been demonstrated in the heart. Little is known about the effects of diet on plasma leptin in the absence of obesity. It was observed that feeding rats a high saturated fat diet for 12 weeks reduced plasma leptin concentrations by 50% compared to normal chow or a high unsaturated fat chow. However, there were no effects on body mass, blood pressure, LV mass, or cardiac function.[255]


Low circulating levels of adiponectin are observed in healthy obese people[237] and are an independent risk factor for hypertension.[256],[257],[258] Adiponectin knockout mice with sodium-induced hypertension demonstrated normalized blood pressure when treated with adiponectin, suggesting that adiponectin exerts a hypotensive action in response to sodium overload.[259]

Aortic banding of adiponectin knockout mice results in enhanced concentric LVH and mortality compared to wild-type animals and is associated with increased activation of extracellular signal-regulated kinase (ERK) and reduced AMPK activation in the heart.[260],[261] Restoration of cardiac adiponectin levels with adenovirus-mediated supplementation partially prevented LVH in response to pressure overload both in adiponectin knockout and wild-type mice and reduced mortality.[260] In addition, adiponectin knockout mice have a larger infarct following ischemia/reperfusion. Treatment with adiponectin reduced infarct size in knockout and wild-type mice. Studies in endothelial cells have shown that adiponectin promotes cell growth and angiogenesis by promoting cross-talk between AMPK and Akt signaling pathways.[262] Taken together, these findings suggest that adiponectin is cardioprotective and anti-hypertrophic and may act through activation of AMPK signaling (as also shown in skeletal muscle).[263] In addition, low levels of adiponectin, such as those present in obesity, may put the heart at risk for LVH and greater injury when subjected to ischemia.[229]

 Molecular Changes Underlying a Transition to Heart Failure

Phenotypically, the mechanisms responsible for the transition from compensated to decompensated hypertrophy includes intrinsic changes in the cardiomyocyte such as re-expression of fetal genes, alterations in the expression and of proteins involved in excitation-contraction (E-C) coupling, and changes in the energetic and metabolic state of the myocytes.[264] The transition to decompensated hypertrophy also includes a mismatch between vascular and cardiomyocyte growth, myocyte death caused by necrosis and apoptosis, and changes in the ECM.[264]

 Impaired Excitation – contraction Coupling

Impaired calcium homeostasis is a prominent feature in the transition from compensatory hypertrophy to heart failure, which manifests as contractile dysfunction and development of arrhythmias.[265] PKCα may be one such regulator that alters calcium handling in the heart and leads to greater decompensation and heart failure.

In the mouse heart activation of PKCα suppresses SR calcium cycling by phosphorylating protein phosphatase inhibitor 1, leading to reduced activity of SERCA2 by rendering phospholamban less phosphorylated.[266] Conversely, hearts of PKCα deficient mice were hyper-contractile and showed increases SR calcium loads and increased phospholamban phosphorylation.[266] PKCα deficient mice were also protected from 3 different models of heart failure, suggesting that this kinase is normally involved in worsening heart disease and promoting decompensation. Similarly, short-term pharmacological inhibition of the conventional PKC isoforms (includes PKCα) significantly augmented cardiac contractility in wild-type mice and in different models of heart failure in vivo, but not in PKCα-deficient mice.[267],[268] Collectively, these results suggest that PKCα inhibition could be a novel therapeutic strategy to antagonize the transition to heart failure by addressing a known dysregulation in calcium homeostasis and contractile performance.[264] S100A1 is a member of the multigenic EF-hand calcium-binding S100 protein family. This calcium sensor co-localizes and interacts both with the SERCA2/phospholamban complex and modulates both systolic and diastolic RyR2 function and cardiomyocyte SR calcium release, respectively.[269] Chronically, failing human myocardium is characterized by progressively diminished S100A1 mRNA and protein levels that inversely correlate with the severity of the disease.[269] That this downregulation might be pathological is consistent with observations in S100A1 null mice that showed enhanced susceptibility to functional deterioration in response to chronic cardiac pressure overload stress and ischemic damage.[270],[271] In contrast, mice with overexpression of S100A1 are hyper-contractile and maintained almost normal left ventricular function following MI.[271]

Vascular and cardiomyocyte growth mismatch

Hypertrophy and cardiomyopathy dynamically alter myocardial oxygen demand and perfusion through the coronary circulation.[264] Pathological hypertrophy is correlated with a reduction in capillary density, possibly leading to myocardial hypoxia or micro-ischemic areas that reinforce pathology.[272] In a mouse model of severe transverse aortic constriction the number of microvessels per cardiomyocyte increases until day 14 (compensated phase) and then decreases thereafter until frank rarefaction is observed (during decompensation).[273]

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that has an essential role in both vasculogenesis and angiogenesis. In addition to endothelial cells, VEGF is also secreted from cardiomyocytes in response to extracellular stimuli.[274] Mice with cardiomyocyte-specific deletion of VEGF-A exhibit reduced capillary density and impaired contractility, suggesting that VEGF secretion from the cardiomyocyte is important for maintenance of cardiac function.[275] Repression of VEGF signaling by an adenoviral vector encoding a decoy VEGF receptor in a murine model of pressure overload hypertrophy resulted in reduced myocardial capillary density, accelerated contractile dysfunction, and pathological cardiac remodeling.[276] Reciprocally, introduction of angiogenic factors during pressure overload enhances the increase in the number of microvessels, preserving the hypertrophic response in a compensated state.[273] Mechanistically, Hif-1α, a key transcription factor for the hypoxic induction of angiogenesis, is increased by pressure overload in the mouse and conditional deletion of this gene resulted in reduced expression of VEGF, lower number of microvessels, significantly attenuated CH and greater heart failure.[273] In the same study, it was shown that p53 accumulation is essential for the transition from CH to heart failure through inhibition of Hif-1α. p53 may induce Hif-1αdegradation through Mdm2, a ubiquitin E3 ligase target gene, although p53-mediated HIF1A ubiquitination and degradation is reversed by the activation of PKB/Akt and independent of Mdm2.[277]

Changes in the extracellular matrix

Ventricular and cellular remodeling in the heart also involves changes in the ECM and associated collagen network that surrounds each cardiac myocytes.[264] Indeed, dynamic changes occur within the interstitium that directly contributes to adverse myocardial remodeling following MI, with hypertensive heart disease and with cardiomyopathy.[278] For example, prolonged pressure overload often results in significantly increased collagen accumulation between individual myocytes and myocytes fascicles.[279] The accumulation of ECM and myocardial fibrosis is directly associated with increased myocardial wall stiffness, which in turn causes the poor filling characteristics in diastole that characterizes early stages of heart failure. In contrast to pressure overload, eccentric hypertrophy from volume overload results in a much different pattern of ECM remodeling.[264]

In large-animal models of volume overload produced by chronic mitral valve regurgitation, the LV remodeling process is accompanied by a distinctive loss of collagen fibrils surrounding individual myocytes.[280] In eccentric hypertrophy, increased ECM proteolytic activity likely contributes to the reduced ECM content and support and thereby facilitates the overall ventricular dilatory process.[278] The matrix metal oproteinases (MMPs) and the endogenous TIMP inhibitors appear to play a major mechanistic role in controlling remodeling of the ECM. For example, mice with global deletion of MMP-9 develop normally in the absence of pathophysiological stress, but they show a reduction in the degree of ventricular dilation and adverse matrix remodeling after MI.[281] Similarly, MMP-2 null mice exhibited a reduction in the rupture rate following MI.[282] Interestingly, pressure overload induced by aortic constriction in MMP-2 null mice showed blunting of the hypertrophic response.[283] Thus, gene deletion of either MMP-9 or MMP-2 was associated with significant effects on myocardial matrix remodeling and whole organ geometry. These findings supported a mechanistic role for both MMP-2 and-9 in adverse myocardial remodeling processes.[264]

Cell death

Cell death is an important mechanism in the development of heart failure and has been reviewed extensively elsewhere.[284] The apoptosis signal-relating kinase (ASK1) appears not to directly regulate CH, but instead alters cell death and propensity to failure in the setting of hypertrophy.[285] Similarly, the BH3 proteins of the Bcl-2 family, Nix, Bnip3, and Puma, promote cell death in the context of hypertrophy[286],[287] underlying the importance of cell death in ventricular remodeling and failure.[264] Protein quality control and degradation appear to be very important for autophagic cell death and hypertrophy.[288]


The process of myocardial hypertrophy, like most biological phenomena, is a highly complex event involving different cell types, in which an entire range of stimuli, membrane receptors, intracellular signaling cascades, transcription factors, genes and effectors bring about, jointly, changes in the architecture and function of the organ. Even though there have been major advances in the identification of molecular regulators involved in this disease process, but the overall complexity of hypertrophic remodeling suggests that additional regulatory mechanisms and targets remain to be identified. The practical implications of the study of the molecular mechanisms that ultimately cause the hypertrophic program to proceed undoubtedly appear to be far off at present. However, the promise of a future gene therapy that will make it possible to limit the development of CH and its progression to heart failure continues to be an attainable goal. However, the battlefronts are not limited to this possibility alone. Interesting prospects are also emerging in other fields, such as the study of polymorphisms and mutations in transcription factors that account for a greater susceptibility to cardiac hypertrophic stimuli, which will enable us to identify molecular risk factors associated with this disease, and to characterize different segments of the population according to their genetic imprint and lifestyle. This, in turn, would allow us to evaluate our resources better and channel them more efficiently.

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Conflicts of interest

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