Abstract 3768: The Deficiency of Ryanodine Receptor Type 2 Accelerates Transition from Adaptive Cardiac Hypertrophy to Dysfunction during Pressure Overload
Alternations of ryanodine receptor type 2 (RyR-2) associate with cardiac hypertrophy and dysfunction, but the mechanism remains elusive. We here examined this by using the mice with heterozygous reduction of RyR-2 gene (RyR-2+/−) and their littermate wild type ones (RyR-2+/+). The mutation induced an impairing of Ca2+ release from sarcoplasmic reticulum (SR) but did not affect growth and morphology of the cardiomyocytes at basal condition. When pressure overload was imposed, comparing to RyR-2+/+ mice, the RyR-2+/− mice displayed an attenuated cardiac hypertrophy and contractibility, the increased death of cardiomyocytes, further down-regulated expression of RyR-2, the different reprogramming of SR Ca2+-ATPase 2, L-type Ca2+ channel and Na1+/Ca2+ exchanger expressions, and a unchanged vasculature reduction in the heart at 3 weeks. Additionally, the decrease of binding of FKBP12.6 to RyR-2 and the increase in phosphorylation of RyR-2 by protein kinase A were aggravated in the loaded RyR-2+/− heart. Furthermore, activation of protein kinase B/Akt and calcineurin by pressure overload was declined whereas that of Ca2+/calmudulin-dependent protein kinase II unchanged in the RyR-2+/− heart comparing the RyR-2+/+ one. These results suggest that reduction of RyR-2 attenuated cardiac hypertrophy but accelerated the development of cardiac dysfunctions through disturbed Ca2+ homeostasis, impaired activation of Akt and calcineurin and increased cardiomyocyte death during pressure overload.