Signaling Involved in Cardiac Hypertrophy
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Signaling Involved in Cardiac Hypertrophy

Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disease with an autosomal dominant pattern of heritability and different penetrance, with a prevalence in the general population of 1/500 (Ref.1) The most proximal initiating stimuli for cardiac hypertrophy can be biomechanical and stretch-sensitive mechanisms, or neurohumoral mechanisms that are associated with the release of hormones, cytokines, chemokines and peptide growth factors. Ligands are sensed by cardiac myocytes through an array of membrane-bound GPCRs. Such signaling circuits directly coordinate hypertrophic growth by altering gene expression in the nucleus and by increasing the rates of protein translation and decreasing the rates of protein degradation in the cytoplasm (Ref.2 and 3).

Many signaling pathways are involved in triggering cardiac hypertrophy in response to hemodynamic stress. Signaling via heterotrimeric Gq/11 proteins is required for pressure overload hypertrophy to develop (Ref.4).Gq-coupled GPCRs that signal through G-alphaq, such as Endothelin receptors and Angiotensin receptors, are believed to play an important role in the pathogenesis of heart failure (Ref.5). The functional classes of cardiovascular receptors correspond to the three major classes of heterotrimeric GTP-binding proteins, G-AlphaS, G-AlphaQ/11, and G-AlphaI. The Beta-Adrenergic Receptors, which couple primarily to G-AlphaS, mediate acute enhancement of heart rate and myocardial contractility in response to epinephrine and norepinephrine stimulation. The second class of myocardial receptors is the cholinergic receptors, typically coupled to G-AlphaI, which are activated by acetylcholine. The third class of receptors, coupled primarily to G-AlphaQ, includes AgtR2, ETRA and ADR-Alpha. All G-proteins consist of the subunits G-Alpha and G-BetaGamma, which upon receptor activation dissociate and independently modulate the activity of downstream signaling effectors, typically AC or PLC. In addition, free G-BetaGamma subunits can directly enhance MAPK signaling, PI3K activity, and Ras signaling in the heart (Ref.4).

Activation of PLC leads to increased hydrolysis of membrane PIP2, the products of which are IP3 and DAG. DAG binds to and activates PKC that phosphorylates numerous substrates. Activation of PKC leads to changes in Ca2+ handling and increase in NHE1 (Ref.5). IP3 binds to IP3R on the surface of the Endoplasmic Reticulum leading to release of Ca2+ ions. The increased Ca2+ levels then activate the protein phosphatase Calcineurin by disrupting the inhibitory effects of Calmodulin. Calcineurin activation leads to the dephosphorylation of NFATc4/NFAT3, allowing it to enter the nucleus, where it cooperates with other transcription factors such as GATA4, CBP, p300, E12 etc., leading to transcription of genes: ANF, Alpha-actin, Beta-myosin, TNF-Alpha, ET1 etc., essential for cardiac development, and thus, hypertrophy. The Adenylosuccinate Synthetase ( ADSS) gene expression is the outcome of the activation of the enhancer region that contains binding sites for NKX2.5, GATA4, E12, Heart And Neural Crest Derivatives Expressed-1 ( HAND1), and HAND2 (Ref.6 and 7).

Receptor-mediated activation of the G-AlphaI subunit results in the direct attenuation of AC in the heart. AC catalyzes the formation of cAMP, which augments myocardial contractility, in part, through a PKA signaling pathway, which directly inhibits phospholamban, promoting increased SERCA activity and augmented calcium handling in the heart. Because G-AlphaI inhibits AC activity, increased expression of G-AlphaI has been predicted to contribute to the pathology of cardiac hypertrophy and heart failure.

The Rho family of small G-proteins, consisting of Rho, Rac, and CDC42 subfamilies, regulates the cytoskeletal organization of cardiomyocytes. Angiotensin-II-stimulated RhoA activation in cardiac myocytes results in the formation of premyofibrils, a function consistent with cytoskeletal organizing capacity (Ref.8). RhoA signaling also stimulates the transcriptional activity of SRF via changes in actin dynamics (Ref.4). Ras, a low-molecular-weight GTPase, is activated by GDP-to-GTP exchange initiated by membrane-bound receptors and upon activation can promote activation of Raf1, PI3K, small GTPase Ral proteins (RalGDS), p120GAP, and p190GAP, leading to Rho activation. In addition, Ras activity is known to result in activation of all three MAPK signaling branches [ERK1/2, JNKs, and p38], all of which participate in the hypertrophic response. Activated Ras was recently shown to promote nuclear localization of NFAT3, thus participating in the NFAT signaling pathway in cardiomyocytes.

MAPK pathways are activated in cardiomyocytes by GPCRs, RTKs (Receptor Tyrosine Kinases), TGF-BetaR (Transforming Growth Factor-Beta Receptor), PKC, Ca2+, or stress stimuli. These upstream events result in the activation of MEKK factors, which leads to the activation of MEK factors, and in turn leads to activation of the three terminal MAPK effectors: JNKs, ERK, and p38. TGF-BetaR regulates MEKs by signaling through TAK1 and TAB1. The MAPKs then phosphorylate other kinases (MAPKAPK1, 2 and 3) and transcription factors (thus regulating transcription). MAPKAPK1 is also known as p90RSK and may also be involved in transcriptional regulation. In addition, MAPKAPK2 and 3 phosphorylate Hsp25/27 and may thereby confer cytoprotection. Activated MAPKs directly phosphorylate serine and threonine residues in a wide array of cytoplasmic proteins and transcription factors, including MAPKAPK2 and 3, E12, ATF2, ATF6Elk1 and c-Jun (Ref.5).

Induction of GP130, a promiscuous receptor for several cytokines, including IL-6, IL-11 (Interleukins), LIF (Leukemia Inhibitory Factor), and CT1 (Cardiotrophin-1) leads to activation of MAPK, PI3K and STAT3 pathways, which results in the induction of genes involved in hypertrophy and survival pathways. Two well-defined direct downstream targets of Akt are likely candidates: GSK3Beta and the mTOR. mTOR then speeds up the process of protein synthesis by activating its downstream targets: p70S6K and 4EBP1/eIF4E. GSK3Beta attenuates hypertrophic signaling by rephosphorylation of NFATc4 that inhibits and phosphorylation of eIF2B, thus inhibiting translation and potentially cardiomyocyte hypertrophy (Ref.4 and 5).