CaMKII Phosphorylation of RyR2 Mediates Heart Failure Development

Abstract

Abnormal regulation of cardiac ryanodine receptor RyR2 by Ca2+/calmodulin‐dependent protein kinase 2 (CaMKII) has been identified as a potential cause of Ca2+ leakage and contractile dysfunction in heart failure. To test the hypothesis that CaMKII phosphorylation of RyR2 is crucial for heart failure development, we generated RyR2 knockin mice in which the CaMKII phosphorylation site S2814 is either mutated into aspartate (SD) to mimic CaMKII phosphorylation, or into alanine (SA) to prevent phosphorylation. Echocardiography revealed a decrease in cardiac function in SD mice at 12 months of age. Both WT and SA mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. At 8 weeks after TAC, SA mice displayed a similar hypertrophic response as WT TAC mice. At 16 weeks after TAC, however, ejection fraction was significantly higher in SA mice compared to WT TAC mice, indicating an inhibition of heart failure development. This rescue effect was further verified by a lower lung‐weight‐to‐tibia‐length ratio and a decrease in expression levels of cardiac stress genes in SA mice. Furthermore, Ca2+ imaging in isolated cardiomyocytes demonstrated a decreased SR Ca2+ leak in SA TAC mice. Our results demonstrate that CaMKII phosphorylation of RyR2 is both sufficient and necessary for heart failure development.R.J.v.O. is recipient of the APS Postdoctoral Fellowship in Physiological Genomics