Abstract 14836: Natriuretic Peptides-Guanylyl Cyclase-A Signaling Pathway Inhibits TRPC6-Mediated Pro-Hypertrophic Signaling in the Hearts
Background: Atrial and brain natriuretic peptides (ANP and BNP, respectively) and their common receptor guanylyl cyclase-A (GC-A), which subsequently activate cGMP-protein kinase G (PKG) signaling pathway, elicits anti-hypertrophic effects. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized. In this study we investigated the effect of ANP-GC-A pathway on transient receptor potential (TRP) C6, a receptor-activated Ca2+ channel, known to be a positive regulator of 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: All these results demonstrate that TRPC6 is a critical target of anti-hypertrophic effect exerted by cardiac natriuretic peptides-GC-A pathway, and suggest a therapeutic potential of TRPC6 blockade for preventing pathological cardiac remodeling.
- © 2010 by American Heart Association, Inc.