CaMKIIδ mediates β-adrenergic effects on RyR2 phosphorylation and SR Ca2+ leak and the pathophysiological response to chronic β-adrenergic stimulation

Chronic activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the deleterious effects of beta-adrenergic receptor (beta-AR) signaling on the heart, in part, by enhancing RyR2-mediated sarcoplasmic reticulum (SR) Ca2+ leak. We used CaMKII delta knockout (CaMKII delta-KO) mice and knockin mice with an inactivated CaMKII site S2814 on the ryanodine receptor type 2 (S2814A) to investigate the involvement of these processes in beta-AR signaling and cardiac remodeling. Langendorff-perfused hearts from CaMKII delta-KO mice showed inotropic and chronotropic responses to isoproterenol (ISO) that were similar to those of wild type (WT) mice; however, in CaMKII delta-KO mice, CaMKII phosphorylation of phospholamban and RyR2 was decreased and isolated myocytes from CaMKII delta-KO mice had reduced SR Ca2+ leak in response to isoproterenol (ISO). Chronic catecholamine stress with ISO induced comparable increases in relative heart weight and other measures of hypertrophy from day 9 through week 4 in WT and CaMKII delta-KO mice, but the development of cardiac fibrosis was prevented in CaMKII delta-KO animals. A 4-week challenge with ISO resulted in reduced cardiac function and pulmonary congestion in WT, but not in CaMKII delta-KO or S2814A mice, implicating CaMKII delta-dependent phosphorylation of RyR2-S2814 in the cardiomyopathy, independent of hypertrophy, induced by prolonged beta-AR stimulation. (C) 2015 Elsevier Ltd. All rights reserved.