BPS2026 - Type 1 ryanodine receptor plays an important role in cardiac hypertrophy by increasing type 2 ryanodine receptor-mediated calcium release

Type 1 ryanodine receptor (RyR1) is predominantly expressed and functionally essential for contractility in skeletal muscle cells. Increasing evidence indicates this Ca 2+ release channel is also expressed in cardiomyocytes. However, its possible function in cardiomyocytes remains elusive. In this study, we sought to address this important question. Transgenic mice overexpressing RyR1 (OE) was generated under α-myosin heavy chain (Myh6) promoter. Surprisingly, but interestingly, these RyR1 OE mice developed cardiac hypertrophy, showing larger whole heart, and ventricular weight. Echocardiography revealed increased left ventricular wall thickness and decreased cardiac output and stroke volume. Using quantitative RT-PCR and western blotting, we found that the RyR1 OE mice had significantly increased RyR1, but not RyR2 and RyR3 expression levels in left ventricle. The cardiac hypertrophic marker genes ANF, BNP, and αSKA mRNA expression levels were markedly elevated in left ventricular cardiomyocytes of RyR1 OE mice. RyR1, but not RyR2 and RyR3, was significantly increased in mice with transverse aortic constriction (TAC) induced cardiac hypertrophy. Similarly, RyR1, but not RyR2, expression was largely increased in cardiac muscle from dogs and humans with heart failure. Maximum 3 H-ryanodine binding was greatly increased, whereas the binding dissociation constant decreased. Ca 2+ spark frequency was significantly increased. The increased Ca 2+ spark was fully blocked by riluzole, a small molecule known to inhibit RyR2, but not RyR1 and RyR3. Reactive oxygen species (ROS) were remarkably increased in RyR1 OE cardiomyocytes. Collectively, our findings demonstrate that RyR1, not RyR2 and RyR3, had a largely increased expression in cardiac muscle from mice with cardiac hypertrophy and dysfunction as well as dog and human with heart failure. Moreover, the potential ROS-dependent RyR2 mediated increased Ca 2+ release is essential for RyR1-induced cardiac hypertrophy and dysfunction.