Ablation of CXCR4 expression in cardiomyocytes exacerbates isoproterenol­induced cell death and heart failure.

ABSTRACT

CXCR4 is a seven­transmembrane­spanning Gi­coupled receptor for the SDF­1 chemokine and plays a critical role in cardiovascular development and post­injury repair. However, the specific role of CXCR4 in cardiomyocytes is incompletely understood. It was hypothesized that CXCR4 activation in cardiomyocytes antagonizes ß­adrenoceptor/Gs signaling­induced cardiac dysfunction. Cardiomyocyte­specific CXCR4 knockout (CXCR4­CMKO) mice were generated by crossing CXCR4fl/fl and MHC­Cre+/­ mice. Their cardiac structure and function in the basal state are equivalent to that of the control MHC­Cre+/­ littermates until at least 4 months old. However, following continuous subcutaneous administration of isoproterenol (Iso) via an osmotic mini­pump, the ventricular myocardial contractility, dilation, cardiomyocyte apoptosis, and interstitial fibrosis are worse in CXCR4­CMKO mice than in MHC­Cre+/­ littermates. In the cultured H9C2 cardiomyocytes, SDF­1 treatment markedly attenuated Iso­induced apoptosis and reduction in phospho­Akt, and this protective effect was lost by knockdown of CXCR4 or by co­treatment with Gi inhibitors. In conclusion, CXCR4 promotes cardiomyocyte survival and heart function during ß­adrenergic stress.