Cardioprotection by CaMKII-δB Is Mediated by Phosphorylation of Heat Shock Factor 1 and Subsequent Expression of Inducible Heat Shock Protein 70

Rationale: Ca2+/calmodulin-dependent protein kinase (CaMK)II is a multifunctional kinase involved in vital cellular processes such as Ca2+ handling and cell fate regulation. In mammalian heart, 2 primary CaMKII isoforms, delta B and delta C, localize in nuclear and cytosolic compartments, respectively. Although previous studies have established an essential role of CaMKII-delta C in cardiomyocyte apoptosis, the functional role of the more abundant isoform, CaMKII-delta B, remains elusive. Objective: Here, we determined the potential role of CaMKII-delta B in regulating cardiomyocyte viability and explored the underlying mechanism. Methods and Results: In cultured neonatal rat cardiomyocytes, the expression of CaMKII-delta B and CaMKII-delta C was inversely regulated in response to H2O2-induced oxidative stress with a profound reduction of the former and an increase of the later. Similarly, in vivo ischemia/reperfusion (IR) led to an opposite regulation of these CaMKII isoforms in a rat myocardial IR model. Notably, overexpression of CaMKII-delta B protected cardiomyocytes against oxidative stress-, hypoxia-, and angiotensin II-induced apoptosis, whereas overexpression of its cytosolic counterpart promoted apoptosis. Using cDNA microarray, real-time PCR and Western blotting, we demonstrated that overexpression of CaMKII-delta B but not CaMKII-delta C elevated expression of heat shock protein (HSP)70 family members, including inducible (i)HSP70 and its homolog (Hst70). Moreover, overexpression of CaMKII-delta B led to phosphorylation and activation of heat shock factor (HSF)1, the primary transcription factor responsible for HSP70 gene regulation. Importantly, gene silencing of iHSP70, but not Hst70, abolished CaMKII-delta B-mediated protective effect, indicating that only iHSP70 was required for CaMKII-delta B elicited antiapoptotic signaling. Conclusions: We conclude that cardiac CaMKII-delta B and CaMKII-delta C were inversely regulated in response to oxidative stress and IR injury, and that in contrast to CaMKII-delta C, CaMKII-delta B serves as a potent suppressor of cardiomyocyte apoptosis triggered by multiple death-inducing stimuli via phosphorylation of HSF1 and subsequent induction of iHSP70, marking both CaMKII-delta isoforms as promising therapeutic targets for the treatment of ischemic heart disease. (Circ Res. 2010;106:102-110.)