Abstract 1834: Inducible Overexpression of Inositol(1,4,5)-trisphosphate receptor type 2 in the Mouse Heart induces Cardiac Hypertrophy
[Introduction] Alterations in intracellular calcium handling is hypothesized to underlie cardiac disease through activating calcium-dependent signaling pathways such as calcineurin (Cn). However the true nature of the calcium alteration that induces reactive signaling remains unknown, especially given the backdrop of cyclical release of calcium in the heart. Calcium release from cardiac inositol (1,4,5)-trisphosphate receptors (IP3R) may produce a specialized microdomain for activating calcium-sensitive signaling pathways. [Hypothesis and Methods] To determine if increased calcium release from IP3R induces or enhances cardiac hypertrophy and deleterious signaling, we generated transgenic (TG) mice with inducible cardiac-specific expression of the mouse type II IP3R (IP3R2). [Results] Two TG lines were characterized. At three months of age, high expressing TG mice showed significant increases in heart weight/body weight (HW/BW) (mg/g) ratio compared to controls (5.86±0.20, n=12 vs 4.77±0.06, n=15; p<0.0001), as well as mild ANF upregulation but no changes in fractional shortening assessed by echocardiography (39.3±0.9% n=12 vs 39.8±1.3% n=7,n.s). Angiotensin II stimulation, which is reported to induce calcium release from IP3R in vitro, exaggerated cardiac hypertrophy in the TG mice compared with controls (6.34±0.16, n=9 vs 5.26±0.28, n=6 in HW/BW ratio, p<0.05). Moreover, IP3R2 TG showed significant increases in HW/BW ratio (7.50±0.2, n=11 vs 6.5±0.3 n=7, p<0.01) following transverse aortic constriction compared with controls, suggesting increased IP3 dependent cardiac signaling is sufficient to enhance pressure overload-induced hypertrophy. Finally, β-adrenergic receptor (βAR) stimulation with isoproterenol also enhanced cardiac hypertrophy in TG mice (7.58±0.13, n=11 vs 5.95±0.1 n=8 in HW/BW ratio, p<0.05). Mechanistically, CnAβ gene targeting blocked the exaggerated increases in HW/BW ratio (7.52±0.15 in TG with Cn Aβ+/+vs 6.20±0.18 in TG with Cn Aβ −/−, n=5 each, p<0.05) induced by βAR stimulation. [Conclusion]Targeted overexpression of IP3R2 in the heart exaggerates cardiac hypertrophy in conjunction with alterations in calcineurin signaling.