期刊
CIRCULATION RESEARCH
卷 106, 期 12, 页码 1849-U153出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.109.208314
关键词
natriuretic peptides; calcium; ion channels; hypertrophy
资金
- Japan Society for the Promotion of Science
- Japanese Ministry of Health, Labour and Welfare
- Mitsubishi Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Uehara Memorial Foundation
- Japan Heart Foundation/Novartis
- Japan Foundation for Applied Enzymology
- Mitsubishi Pharma Research Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Kanae Foundation for the Promotion of Medical Science
- Ichiro Kanehara Foundation
- Suzuken Memorial Foundation
- Vehicle Racing Commemorative Foundation
- Japan Research Promotion Society for Cardiovascular diseases
- Takeda Medical Research Foundation
- Hohansha Foundation
- Kimura Memorial Heart Foundation
- Grants-in-Aid for Scientific Research [21590246, 22681033, 22689003, 20249015] Funding Source: KAKEN
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 Ca2+ 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 Ca2+ 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. (Circ Res. 2010;106:1849-1860.)
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