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

Abstract Heart failure is an ageing-associated disease. CXCR4, a seven-transmembrane-spanning Gi-coupled receptor for the SDF-1 chemokine, plays a critical role in organogenesis, healthy ageing, vascular post-injury repair and regeneration; however, the specific role of cardiomyocyte CXCR4 in heart function and the pathogenesis of heart failure is incompletely understood. We hypothesize that CXCR4 expression in cardiomyocytes is protective during β-adrenoceptor/Gs stress-induced cardiac dysfunction. Cardiomyocyte-specific CXCR4 knockout (CXCR4-CMKO) mice were generated by crossing CXCR4fl/fl and MHC-Cre+/− mice and shown to display normal cardiac structure and function in the basal state until at least 4 months old. However, following continuous administration of isoproterenol (Iso) via an osmotic mini-pump, their ventricular myocardial contractility, dilation, cardiomyocyte apoptosis, and interstitial fibrosis were worsened compared to that of control MHC-Cre+/− littermates under same treatment. In the cultured H9C2 cardiomyocytes, SDF-1 treatment markedly attenuated Iso-induced apoptosis and reduction in phospho-Akt, and these protective effects were diminished by knockdown of CXCR4 or by co-treatment with Gi inhibitors. Thus, cardiomyocyte SDF-1/CXCR4 signaling alleviates β-adrenergic stress-induced cell death and cardiac adverse remodeling, thus may be harnessed for treatment of heart failure.