Abstract 14519: CXCR4 Protects Cardiomyocytes From Beta-Adrenergic Stress-Induced Apoptosis
Introduction: The Gi protein-coupled receptor CXCR4 is being validated as a therapeutic target for recruitment of progenitor cells for cardiovascular repair; however, its function in cardiomyocytes is unknown.
Methods and Results: To assess the relative expression of CXCR4 and its ligand SDF-1 in vivo, we generated CXCR4BAC:eGFP;SDF1BAC:SDF-1-RFP double transgenic reporter mice. SDF-1 (red) is expressed in cardiomyocytes and distributed evenly in the extracellular space; CXCR4 (green) is expressed intensively in endothelial cells. To investigate the cardiomyocyte-specific function of CXCR4, we generated MHC:Cre+/-;CXCR4fl/fl (KO) mice and MHC:Cre+/-;CXCR4+/+ (WT) littermate controls. Echocardiography assessments of heart function revealed no difference between the KO and WT mice at ages up to 4 months (n=30). Because CXCR4 expression is up-regulated in the failing heart in patients and an increased β-adrenergic activity contributes to the pathogenesis of heart failure, we investigated whether cardimyocyte CXCR4 plays a role in maintaining heart function during β-adrenergic stress. Isoproterenol (Iso) was continuously administered to WT and KO mice (45 mg/kg/day) via mini-pumps. Heart function was assessed at days 0, 3, 7, and 14; the KO mice exhibited a significantly lower LV ejection fraction (P<0.05 at days 7 and 14; n=15) and thinner LV anterior wall (P<0.05 at systole at day14) than WT mice. Histological analyses of heart tissues revealed a significantly greater amount of apoptotic cardiomyocytes (TUNEL staining, P<0.01 at day 14) and larger fibrosis area (Sirius red staining, P<0.01) in the stressed myocardium of KO mice than in that of WT controls. In vitro, iso (10 uM) treatment for 24h induced prominent apoptosis in H9C2 cardiomyocytes, which was significantly attenuated by co-treatment with SDF-1 (p<0.001, n=6). Importantly, the SDF-1-mediated protective effect was abolished by addition of a Gi inhibitory peptide or by siRNA-mediated CXCR4 knock-down.
Conclusion: Genetic deletion of CXCR4 in cardiomyocytes increases their susceptibility to β-adrenergic stress-induced apoptosis; CXCR4 may play a protective role during heart failure.
- © 2011 by American Heart Association, Inc.