Ablation of CXCR4 expression in cardiomyocytes exacerbates isoproterenol-induced cell death and heart failure

CXCR4 is a seven-transmembrane-spanning Gi-coupled receptor for the SDF-1 chemokine and plays a critical role in cardiovascular development and post-injury repair. However, the specific role of CXCR4 in cardiomyocytes is incompletely understood. It was hypothesized that CXCR4 activation in cardiomyocytes antagonizes β-adrenoceptor/Gs signaling-induced cardiac dysfunction. Cardiomyocyte-specific CXCR4 knockout (CXCR4-(CM)KO) mice were generated by crossing CXCR4(fl/fl) and MHC-Cre(+/−) mice. Their cardiac structure and function in the basal state are equivalent to that of the control MHC-Cre(+/−) littermates until at least 4 months old. However, following continuous subcutaneous administration of isoproterenol (Iso) via an osmotic mini-pump, the ventricular myocardial contractility, dilation, cardiomyocyte apoptosis, and interstitial fibrosis are worse in CXCR4-(CM)KO mice than in MHC-Cre(+/−) littermates. In the cultured H9C2 cardiomyocytes, SDF-1 treatment markedly attenuated Iso-induced apoptosis and reduction in phospho-Akt, and this protective effect was lost by knockdown of CXCR4 or by co-treatment with Gi inhibitors. In conclusion, CXCR4 promotes cardiomyocyte survival and heart function during β-adrenergic stress.