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

• Published in: Circulation research 2010-09, Vol.107 (5), p.667-676
• Main Authors: Agarwal, Udit, Ghalayini, Wael, Dong, Feng, Weber, Kristal, Zou, Yong-Rui, Rabbany, Sina Y, Rafii, Shahin, Penn, Marc S
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cardiac Myosins - genetics; Cardiology. Vascular system; Cell Movement; Cells, Cultured; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Coronary heart disease; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Heart; Integrases - genetics; Male; Medical sciences; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Myosin Heavy Chains - genetics; Myosin Light Chains - genetics; Receptors, CXCR4 - deficiency; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; RNA, Messenger - metabolism; Time Factors; Transfection; Ventricular Function, Left; Ventricular Remodeling; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.110.223289

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 mice were generated by crossing CXCR4 mice with MCM-Cre mouse and MLC2v-Cre mouse on the C57BL/6J background, yielding CXCR4 MCM-Cre and CXCR4MLC2v-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 CXCR4MLC2v-Cre are viable, had normal cardiac function, and had no evidence of ventricular septal defect. CXCR4MCM 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 mice versus CM-CXCR4 mice regardless of strategy of Cre expression. No differences in vascular density (2369±131 versus 2471±126 vessels/mm; CXCR4 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.