title: Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart.
abstract: 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.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduated School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.forename: Zhong
authors.initials: Z
authors.lastname: Jian
authors.forename: Xianglu
authors.initials: X
authors.lastname: Rong
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kiyonaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
authors.forename: Ryuji
authors.initials: R
authors.lastname: Inoue
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Li
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Usami
authors.forename: Masataka
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Takeya
authors.initials: T
authors.lastname: Minami
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: 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
chemical_list: 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