Inhibition of TRPC6 Channel Activity Contributes to the Antihypertrophic Effects of Natriuretic Peptides-Guanylyl Cyclase-A Signaling in the Heart

• Published in: Circulation research Vol. 106; no. 12; pp. 1849 - 1860
• Main Authors: Kinoshita, Hideyuki, Kuwahara, Koichiro, Nishida, Motohiro, Jian, Zhong, Rong, Xianglu, Kiyonaka, Shigeki, Kuwabara, Yoshihiro, Kurose, Hitoshi, Inoue, Ryuji, Mori, Yasuo, Li, Yuhao, Nakagawa, Yasuaki, Usami, Satoru, Fujiwara, Masataka, Yamada, Yuko, Minami, Takeya, Ueshima, Kenji, Nakao, Kazuwa
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 25.06.2010; Lippincott Williams & Wilkins
• Subjects: Anilides - pharmacology; Animals; Atrial Natriuretic Factor - metabolism; Biological and medical sciences; Calcium Channels - metabolism; Cells, Cultured; Cyclic GMP - metabolism; Cyclic GMP-Dependent Protein Kinases - metabolism; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Humans; Hypertrophy - metabolism; Hypertrophy - pathology; Hypertrophy - prevention & control; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Natriuretic Peptide, Brain - metabolism; NFATC Transcription Factors - metabolism; Patch-Clamp Techniques; Rats; Receptors, Atrial Natriuretic Factor - genetics; Receptors, Atrial Natriuretic Factor - metabolism; Signal Transduction - physiology; Thiadiazoles - pharmacology; TRPC Cation Channels - antagonists & inhibitors; TRPC Cation Channels - metabolism; Vertebrates: cardiovascular system; Heart; Calcium; Peptides; Enzyme; Phosphorus-oxygen lyases; Lyases; Ionic channel; Guanylate cyclase; Inorganic element; ion channels; Signal transduction; natriuretic peptides; Vertebrata; Mammalia; Circulatory system; Inhibition; Hypertrophy
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.208314

RATIONALE:Atrial and brain natriuretic peptides (ANP and BNP, respectively) exert antihypertrophic effects in the heart via their common receptor, guanylyl cyclase (GC)-A, which catalyzes the synthesis of cGMP, leading to activation of protein kinase (PK)G. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized. OBJECTIVE:We investigated the effect of ANP-GC-A signaling on transient receptor potential subfamily C (TRPC)6, a receptor-operated Ca channel known to positively regulate prohypertrophic calcineurin–nuclear factor of activated T cells (NFAT) signaling. METHODS AND RESULTS:In cardiac myocytes, ANP induced phosphorylation of TRPC6 at threonine 69, the PKG phosphorylation site, and significantly inhibited agonist-evoked NFAT activation and Ca influx, whereas in HEK293 cells, it dramatically inhibited agonist-evoked TRPC6 channel activity. These inhibitory effects of ANP were abolished in the presence of specific PKG inhibitors or by substituting an alanine for threonine 69 in TRPC6. In model mice lacking GC-A, the calcineurin-NFAT pathway is constitutively activated, and BTP2, a selective TRPC channel blocker, significantly attenuated the cardiac hypertrophy otherwise seen. Conversely, overexpression of TRPC6 in mice lacking GC-A exacerbated cardiac hypertrophy. BTP2 also significantly inhibited angiotensin II–induced cardiac hypertrophy in mice. CONCLUSIONS:Collectively, these findings suggest that TRPC6 is a critical target of antihypertrophic effects elicited via the cardiac ANP/BNP-GC-A pathway and suggest TRPC6 blockade could be an effective therapeutic strategy for preventing pathological cardiac remodeling.