Role of Cardiac Myocyte CXCR4 Expression in Development and Left Ventricular Remodeling After Acute Myocardial Infarction

Abstract

Rationale: Stromal cell–derived factor (SDF)-1/CXCR4 axis has an instrumental role during cardiac development and has been shown to be a potential therapeutic target for optimizing ventricular remodeling after acute myocardial infarction (AMI) and in ischemic cardiomyopathy. Although a therapeutic target, the specific role of cardiac myocyte CXCR4 (CM-CXCR4) expression following cardiogenesis and survival of cardiac myocyte and left ventricular remodeling after AMI is unknown. Objective: We hypothesized that cardiac myocyte derived CXCR4 is critical for cardiac development, but it may have no role in adulthood secondary to the short transient expression of SDF-1 and the delayed expression of CM-CXCR4 following AMI. To address this issue, we developed congenital and conditional CM-CXCR4 −/− mouse models. Methods and Results: Two strains of CM-CXCR4 flox/flox mice were generated by crossing CXCR4 flox/flox mice with MCM-Cre +/− mouse and MLC2v-Cre +/− mouse on the C57BL/6J background, yielding CXCR4 flox/flox MCM-Cre +/− and CXCR4 flox/flox MLC2v-Cre +/− mice. Studies demonstrated recombination in both models congenitally in the MLC2v-Cre +/− mice and following tamoxifen administration in the MCM-Cre +/− mice. Surprisingly the CXCR4 flox/flox MLC2v-Cre +/− are viable, had normal cardiac function, and had no evidence of ventricular septal defect. CXCR4 flox/flox MCM +/− treated with tamoxifen 2 weeks before AMI demonstrated 90% decrease in cardiac CXCR4 expression 48 hours after AMI. Twenty-one days post AMI, echocardiography revealed no statistically significant difference in the wall thickness, left ventricular dimensions or ejection fraction (40.9±7.5 versus 34.4±2.6%) in CXCR4 flox/flox mice versus CM-CXCR4 −/− mice regardless of strategy of Cre expression. No differences in vascular density (2369±131 versus 2471±126 vessels/mm 2 ; CXCR4 flox/flox versus CM-CXCR4 −/− mouse), infarct size, collagen content, or noninfarct zone cardiac myocyte size were observed 21 days after AMI. Conclusions: We conclude that cardiac myocyte–derived CXCR4 is not essential for cardiac development and, potentially because of the mismatch in timings of peaks of SDF-1 and CXCR4, has no major role in ventricular remodeling after AMI.