TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy

Abstract

Angiotensin (Ang) II participates in the pathogenesis of heart failure through induction of cardiac hypertrophy. Ang II-induced hypertrophic growth of cardiomyocytes is mediated by nuclear factor of activated T cells (NFAT), a Ca 2 þ -responsive transcriptional factor. It is believed that phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP 3 ) is responsible for Ca 2 þ increase that is necessary for NFAT activation. However, we demonstrate that PLC-mediated production of diacylglycerol (DAG) but not IP 3 is essential for Ang II-induced NFAT activation in rat cardiac myocytes. NFAT activation and hypertrophic responses by Ang II stimulation required the enhanced frequency of Ca 2 þ oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca 2 þ channel. Patch clamp recordings from single myocytes revealed that Ang II activated DAG-sensitive TRPC-like currents. Among DAG-activating TRPC channels (TRPC3, TRPC6, and TRPC7), the activities of TRPC3 and TRPC6 channels correlated with Ang II-induced NFAT activation and hypertrophic responses. These data suggest that DAGinduced Ca 2 þ signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy.

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).…”

“…More provocatively, TRPC channels probably coexist with TRPM and TRPP subclasses of channels in even larger channel complexes (16,17). Because all TRPC family members have been detected in the heart, some of which are up-regulated by hypertrophy (4)(5)(6)(7)23), it is likely that many combinations of tetramers are possible and can generate unique cation influx properties. However, combined inhibition of both subfamilies in dnTRPC4, dnTRPC3 DTG mice completely eliminated all TAC-associated Ca 2+ entry, suggesting that not all TRPC complexes show crossoligomerization in the heart.…”

“…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).…”

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

“…Nakayama et al (71) showed that calcineurin/NFAT-mediated signaling and hypertrophy were dependent on TRPC4. In addition, TRPC3 and TRPC6 have also been shown to contribute to the development of ANG II-induced hypertrophy (79), and SOCE and NFAT translocation have been shown to be increased in HEK293 cells overexpressing TRPC1 (78). Interestingly, as recently as 2011, although describing the significance of SOCE in cardiomyocytes as a mystery, Eder and Molkentin nevertheless concluded that "TRPC channels are bona fide regulators of cardiac hypertrophy associated with pathological events and neuroendocrine signaling" (18).…”

Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y 2 receptor stimulation through S-nitrosylation of NF-κB

“…Expression level of AT 1 R in rat neonatal cardiac fibroblasts is more than fivefold higher than that in rat neonatal cardiomyocytes (65 ± 12 fmol/mg protein), and AT 1 R signaling in cardiac fibroblasts has been implicated in the development of cardiac fibrosis (17). We have previously reported that treatment with Ang II increases activity of nuclear factor of activated T cells (NFAT), a Ca 2+ -dependent transcriptional factor that is predominantly regulated by calcineurin, both in cardiac myocytes and fibroblasts (18,19). Activation of NFAT has been implicated in the development of cardiac hypertrophy (20), but the role of NFAT in cardiac fibroblasts is not fully known.…”