Canonical Transient Receptor Potential Channels Promote Cardiomyocyte Hypertrophy through Activation of Calcineurin Signaling

Abstract

The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in the control of cardiomyocyte hypertrophy in response to pathological stimuli. Although calcineurin is present at high levels in normal heart, its activity appears to be unaffected by calcium during the course of a cardiac cycle. The mechanism(s) whereby calcineurin is selectively activated by calcium under pathological conditions has remained unclear. Here, we demonstrate that diverse signals for cardiac hypertrophy stimulate expression of canonical transient receptor potential (TRPC) channels. TRPC consists of a family of seven membrane-spanning nonselective cation channels that have been implicated in the nonvoltage-gated influx of calcium in response to G protein-coupled receptor signaling, receptor tyrosine kinase signaling, and depletion of internal calcium stores. TRPC3 expression is up-regulated in multiple rodent models of pathological cardiac hypertrophy, whereas TRPC5 expression is induced in failing human heart. We demonstrate that TRPC promotes cardiomyocyte hypertrophy through activation of calcineurin and its downstream effector, the nuclear factor of activated T cells transcription factor. These results define a novel role for TRPC channels in the control of cardiac growth, and suggest that a TRPC-derived pool of calcium contributes to selective activation of calcineurin in diseased heart. Cardiac hypertrophy is an adaptive response of the heart to many forms of cardiac disease, including hypertension, mechanical load abnormalities, myocardial infarction, valvular dysfunction, cardiac arrhythmias, endocrine disorders, and genetic mutations in cardiac contractile protein genes. Whereas the hypertrophic response is thought to be an initially compensatory mechanism that augments cardiac performance, sustained hypertrophy is maladaptive and frequently leads to ventricular dilation and the clinical syndrome of heart failure. Accordingly, cardiac hypertrophy has been established as an independent risk factor for cardiac morbidity and mortality (1).Abnormal calcium handling, characterized by elevated intracellular diastolic calcium levels, is a hallmark of cardiac hypertrophy and heart failure. Elevated intracellular calcium not only impairs the contractile performance of the heart, but also activates calcium-dependent signaling pathways that mediate maladaptive cardiac remodeling (2). One such pathway is regulated by the calcium-calmodulin-dependent phosphatase calcineurin, which has been shown to be sufficient, and in some cases, necessary for pathological hypertrophy (3-5). Activated calcineurin dephosphorylates the transcription factor nuclear factor of activated T-cells (NFAT), 4 facilitating translocation of NFAT to the nucleus where it acts in concert with other proteins to mediate expression of prohypertrophic genes. The activity of calcineurin is tightly regulated in vivo by a negative feedback mechanism; one of the most highly sensitive NFAT target genes encodes a potent calcineurin inhibitor, modulatory calcineuri...

TRPC channels are necessary mediators of pathologic cardiac hypertrophy

“…Simple overexpression of TRPC3 or TRPC6 in the mouse heart was sufficient to induce Ca 2+ entry and enhance the cardiac hypertrophic response (4,5). Mechanistically, we and others have shown that TRPC channels engage calcineurin-NFAT signaling in the heart, a well-known prohypertrophic pathway that is both necessary and sufficient for growth (4)(5)(6)(7). Indeed, deletion of calcineurin Aβ reduced hypertrophic inducibility by TRPC3 overexpression in the heart (5).…”

“…Similarly, induction of TRPC channel activity during cardiac hypertrophy is hypothesized to generate a distinct Ca 2+ signaling microdomain that can impact calcineurin signaling and the hypertrophic response directly (21). Simple overexpression of TRPC3 or TRPC6 in the mouse heart was sufficient to induce Ca 2+ entry and enhance the cardiac hypertrophic response (4,5). Mechanistically, we and others have shown that TRPC channels engage calcineurin-NFAT signaling in the heart, a well-known prohypertrophic pathway that is both necessary and sufficient for growth (4)(5)(6)(7).…”

“…Overexpression of TRPC3 or -6 was reported to induce cardiac hypertrophy through calcineurin/NFAT signaling in transgenic (TG) mice (4,5). More recently, some data have emerged suggesting that TRPC channels are required for cardiac hypertrophy, because Trpc1 −/− mice and use of the TRPC3 inhibitory compound Pyr3 showed reduced pressure-overload growth (10,11).…”

“…Augmentation in intracellular Ca 2+ is thought to be critically involved in signaling cardiac hypertrophy, in part through the Ca 2+ -activated protein phosphatase calcineurin, which leads to activation of the transcription factor, nuclear factor of activated T cells (NFAT), which induces hypertrophic response genes (3). Transient receptor potential canonical (TRPC) channels are cation-selective influx channels that can initiate cardiac hypertrophy when overexpressed, in part because of increased Ca 2+ influx and calcineurin activation (4)(5)(6)(7). Functional TRPC channels are comprised of homo-or heterotetramers between either TRPC1/4/5 or TRPC3/ 6/7 subfamily members, although overexpression of any one subunit alone can produce enhanced currents (8).…”

TRP Channels: Their Function and Potentiality as Drug Targets

“…For example, α1 adrenergic receptorstimulated hypertrophic responses were blocked by 2-aminoethoxydiphenylborane (2-APB) and N-{4-[3,5-bis(trifl uoromethyl)-1H-pyrazol-1yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide (BTP2; also called Pyr2), but not by verapamil, a voltage-dependent L-type Ca 2+ channel blocker [ 142 ]. Indirect inhibition of TRPC3/6 channel activities by PDE-5 inhibitors [ 159 ] and ANP [ 158 ] can also suppresses pathological hypertrophy through phosphorylation of TRPC6 at Thr69.…”