Chemokines in healing myocardial infarction

ABSTRACT: Cell-extracellular matrix (ECM) communication is mediated through the integrins, a family of heterodimeric cell surface receptors that bind to ECM ligands and modulate a wide range of cellular responses. Although integrins have been implicated in regulation of inflammation, fibrosis and angiogenesis, their involvement in post-infarction repair and remodeling remains poorly understood. Our proposal investigates for the first time the cell-specific roles of integrin signaling in myocardial infarction (MI). Our preliminary data demonstrate cell-specific roles of 5 integrin (ITGA5) in cardiac repair and post-infarction remodeling: macrophage ITGA5 protects the infarcted heart stimulating angiogenesis, whereas fibroblast ITGA5 promotes dysfunction accentuating myofibroblast infiltration in the infarct border zone. Moreover, V integrin (ITGAV) is markedly upregulated in infarct macrophages and plays a central role in regulation of macrophage phenotype. Accordingly, we hypothesize that macrophages and fibroblasts sense changes in the ECM composition of the infarct through integrins, and activate cellular responses critical for repair, remodeling and fibrosis of the infarcted heart. This hypothesis will be tested in 3 specific aims: Aim 1: To dissect the mechanisms responsible for the protective effects of macrophage-specific ITGA5 signaling in the infarcted heart. We demonstrated that macrophage ITGA5 protects from adverse post-MI remodeling through actions that may involve (in part) stimulation of an angiogenic macrophage phenotype. Accordingly, we will dissect the mechanisms responsible for integrin-mediated activation of macrophages, and we will examine the relation between integrin expression and macrophage heterogeneity in healing infarcts. Aim 2: To study the role of fibroblast and myofibroblast ITGA5 in the infarcted and remodeling heart. Our preliminary data show ITGA5 upregulation in activated fibroblasts and myofibroblasts infiltrating the infarct and suggest that fibroblast-specific ITGA5 mediates dysfunction and adverse remodeling. Accordingly, we will use cell-specific integrin KO mice and in vitro assays to explore the role of ITGA5 in regulation of fibroblast phenotype and we will dissect the molecular cascades mediating ITGA5-stimulated responses. Aim 3: To investigate the role of macrophage ITGAV in repair and remodeling of the infarcted heart and to dissect ITGAV-dependent mechanisms of macrophage activation. Our preliminary data show that infarct macrophages exhibit ITGAV upregulation and that ITGAV blockade modulates the fibrogenic profile of macrophages. Accordingly, we will use myeloid cell- and inducible macrophage-specific ITGAV KO mice and in vitro experiments to investigate the role of macrophage ITGAV in repair, remodeling and fibrosis of the infarcted heart and to dissect the molecular mechanisms responsible for ITGAV actions. The proposed studies will greatly contribute to our understanding of ECM:cell interactions in the infarcted heart. Considering the availability of integrin inhibitors, our experiments have important therapeutic implications.