Anti-Remodeling Effects of the CXCL12/CXCR4 Axis in the Cardiac Myocyte

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DESCRIPTION (provided by applicant): The chemokine, CXCL12 (also known as Stromal Cell Derived Factor-1, SDF-1) and its major receptor, CXCR4, have been described to play a critical role in recruitment of stem cells to areas of myocardial infarction (Ml). The increased expression of CXCL12 in ischemic tissue acts as a cellular signal to attract potentially beneficial stem cells to repair, and possibly regenerate, damaged myocardium by preventing apoptosis, inducing angiogenesis and inhibiting fibrosis, all leading to a preservation of global cardiac function. However, the main hypothesis of stem cells differentiating into new cardiac myocytes to provide benefit has been largely unproven. This has led to an increased interest in identifying paracrine mechanisms of stem cells in the myocardium. Studies have demonstrated overexpression of CXCL12 in various types of stem cells enhances cardiac performance post-Mi by not only angiogenic and anti-apoptotic mechanisms, but also through inhibition of myocardial remodeling. Therefore, the immediate goal of this proposal is to investigate the role of the stem cell secretory factor, CXCL12, on remodeling mechanisms in the cardiac myocyte. This proposal will focus on a phenylephrine (PE)-induced pathological hypertrophy model. Hence, our hypothesis entails CXCL12 preventing PE-induced pathological hypertrophy in the cardiac myocyte by a beneficial, anti-remodeling mechanism. 1) We will determine whether the CXCL12/CXCR4 axis is a molecular determinant in modulating PE-induced hypertrophic responses in the cardiac myocyte in vitro by assessing protein synthesis, ANF mRNA expression, myofilament organization and cell size. Next, the effect of CXCL12 on diastolic calcium accumulation will also be measured. 2) We will investigate the mechanism by which CXCL12 regulates PE-induced cardiac myocytehypertrophy, focusing on three major regulatory nodes of hypertrophy signaling: Calcineurin/NFAT, MAP Kinases, and GSK3B. 3) We will define the physiological consequences of the over-expression and ablation of cardiac CXCR4 on PE-induced hypertrophy in vivo. Adeno-associated virus-9 (AAV9) will be used as a vector to perform over-expression myocardial gene transfer of CXCR4. Cardiac function and structure will be assessed by in vivo hemodynamics, ANF/BNP expression, heart weight:body weight ratio, and histology. PUBLIC HEALTH RELEVANCE: The results from this proposal will provide insights into a new modulatory mechanism of CXCR4 upon myocardial remodeling. The further investigation of CXCR4 signaling in the adult cardiac myocyte may help in the generation and refinement of new approaches to stem cell based therapies for cardiac disease.