The IP 3 Receptor Regulates Cardiac Hypertrophy in Response to Select Stimuli

Abstract

Rationale: Inositol 1,4,5-trisphosphate (IP 3 ) is a second messenger that regulates intracellular Ca 2+ 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 IP 3 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 IP 3 receptor signaling to examine its hypertrophic growth effects following pathological and physiological stimulation. Methods and Results: Overexpression of the mouse type-2 IP 3 receptor (IP 3 R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca 2+ transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP 3 R2 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 IP 3 signaling in vivo, we generated transgenic mice expressing an IP 3 chelating protein (IP 3 -sponge). IP 3 -sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP 3 R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-Aβ–null background. Conclusion: These results indicate that IP 3 -mediated Ca 2+ release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.