Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart.
BACKGROUND
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(2+) channel known to positively regulate prohypertrophic calcineurin-nuclear factor of activated T cells (NFAT) signaling.


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(2+) 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.
Kinoshita
Hideyuki
H
Department of Medicine and Clinical Science, Kyoto University Graduated School of Medicine, Kyoto 606-8507, Japan.
Kuwahara
Koichiro
K
Nishida
Motohiro
M
Jian
Zhong
Z
Rong
Xianglu
X
Kiyonaka
Shigeki
S
Kuwabara
Yoshihiro
Y
Kurose
Hitoshi
H
Inoue
Ryuji
R
Mori
Yasuo
Y
Li
Yuhao
Y
Nakagawa
Yasuaki
Y
Usami
Satoru
S
Fujiwara
Masataka
M
Yamada
Yuko
Y
Minami
Takeya
T
Ueshima
Kenji
K
Nakao
Kazuwa
K
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D013830:Thiadiazoles / Q000494:pharmacology
C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D015220:Calcium Channels; D050778:NFATC Transcription Factors; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D013830:Thiadiazoles; C492146:Trpc6 protein, mouse; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D017869:Cyclic GMP-Dependent Protein Kinases; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP