CAVEOLIN-1 IN CARDIAC REMODELING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this study is to determine the role of caveolae in myocardial remodeling after myocardial infarction. In cardiac fibrosis, fibrous tissue replaces healthy contractile tissue. Increased fibrous tissue also decreases capillary density and increases the distance oxygen must diffuse, leading to hypoxia of myocytes with dysfunction, dysrhythmia, and eventual replacement by non-contractile fibroblasts. The regulation of these processes is controlled in large part by transforming growth factor TGF-beta. A better understanding of the regulation of the TGF-beta signaling pathway in cardiac remodeling could lead to improved treatment or prevention of this complication of myocardial infarction. We recently demonstrated that reduced expression of caveolin-1 (cav1) leads to enhanced TGF-beta signaling in airway remodeling. Cav1 regulates TGF-beta activity by either preventing signal transduction initiated by the TGF-beta receptors complex or enhancing the degradation of the TGF-beta receptors complex. We therefore hypothesize that the inflammatory response following myocardial infarction contributes to cardiac remodeling by promoting TGF-beta signaling via a cav1-dependent mechanism. The specific aims of this proposal are:1) Determine whether myocardial inflammation decreases cav1 expression after myocardial infarction. We hypothesize that cytokines expressed in myocardial inflammation following infarct downregulates cav1 expression leading to TGF-beta signaling enhancement. We will compare cav1 expression in wild type mice in infarcted and non-infarcted tissue and examine the activation of TGF-beta signaling. 2) Explicate the mechanism by which IL-6 regulates the compartmentalization of TGF-beta receptors and thereby promotes TGF-beta signaling. We hypothesize that IL-6 promotes the partitioning of TGF-beta receptors into non-cav1 vesicles and therefore reduced TGF-beta receptor turnover and promoting signaling. 3) Determine how genetic ablation of cav1 modulates TGF-beta signaling. We hypothesize that cav1-deficiency enhances TGF-beta effects in myocardial remodeling. We will compare the TGF-beta activation of Smad signaling in infarcted tissues in wild type and cav1-deficient mice. We will also identify potential new regulatory mechanisms that are cav1-independent.