Rationale: Inositol 1,4,5-trisphosphate (IP3) is a second messenger that regulates intracellular Ca2+ release through IP 3 receptors located in the sarco(endo)plasmic reticulum of cardiac myocytes. Many prohypertrophic G protein-coupled receptor (GPCR) signaling events lead to IP3 liberation, although its importance in transducing the hypertrophic response has not been established in vivo. Objective: Here, we generated conditional, heart-specific transgenic mice with both gain-and loss-of-function for IP3 receptor signaling to examine its hypertrophic growth effects following pathologiCa2+ and Physiological stimulation. Methods and Results: Overexpression of the mouse type-2 IP 3 receptor (IP3R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca2+ transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP3R2 overexpression failed to augment/synergize cardiac hypertrophy following 2 weeks of pressure-overload stimulation, such levels did enhance hypertrophy following 2 weeks of isoproterenol infusion, in response to Gαq overexpression, and/or in response to exercise stimulation. To inhibit IP3 signaling in vivo, we generated transgenic mice expressing an IP3 chelating protein (IP3-sponge). IP3-sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP3R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-Aβ-null background. Conclusion: These results indicate that IP3-mediated Ca2+ release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine