Abstract 16518: Inhibition of Inositol (1,4,5)-Trisphosphate Signaling in the Mouse Heart Attenuates Cardiac Hypertrophy after GPCR Stimulation.
Introduction: Alterations in intracellular calcium (Ca2+) handling is hypothesized to underlie cardiac disease through activating calcium-dependent signaling pathways such as calcineurin. However the true nature of the Ca2+ alteration that induces reactive signaling remains unknown, especially given the backdrop of cyclical release of Ca2+ in the heart. Ca2+ release from cardiac inositol (1,4,5)-trisphosphate (IP3) receptors may produce a specialized microdomain for activating calcium-sensitive signaling pathways. IP3-sponge (IP3SP) is a recombinant protein generated from IP3 binding core in IP3 receptor (IP3R) which displays 500-fold higher affinity to IP3 compared with IP3Rs and inhibits IP3 signaling by chelating IP3 in vitro.
Hypothesis and Methods: To determine if inhibition of Ca2+ release from IP3R attenuates cardiac growth and deleterious signaling, we generated transgenic (TG) mice with cardiac-specific expression of the IP3SP protein. [Results] Two TG lines were obtained and the higher expressing line was characterized. In adult cardiomyocytes, IP3SP expression alleviated alterations of Ca2+ transients after endothelin-1 stimulation, suggesting chelating IP3 by transgene is physiologically functional. IP3SP TG mice showed no overt cardiac phenotype in terms of heart weight/body weight (HW/BW) (mg/g) ratio, fibrosis and fetal gene expression at three months of age. Angiotensin II stimulation, which is reported to induce Ca2+ release from IP3R in vitro, mediated less cardiac hypertrophy in the TG mice compared with controls (5.1±0.1, n=5 vs 5.9±0.7, n=5 in HW/BW ratio, p<.05). In addition, chronic PKA activation, which is reported to phosphorylate IP3Rs and sensitize its Ca2+ release in response to IP3, also elicited less cardiotrophic responses in IP3SP TG mice (5.7±0.1, n=6 vs 6.4±0.2 n=7 in HW/BW ratio, p<.05). In contrast, IP3SP expression failed to mitigate cardiac growth in HW/BW ratio (7.1±0.2, n=5 vs 6.9±0.2 n=8, n.s) following transverse aortic constriction. Thus, our results suggest IP3 signaling regulates cardiac hypertrophy in response to select stimuli. [Conclusion] Targeted inhibition of IP3 signaling in the heart attenuates cardiac hypertrophy in response to G-protein coupled receptor stimulation.
- © 2010 by American Heart Association, Inc.