Epicardial remodeling in cardiomyopathy and cardiac aging

Mayo Clinic Rochester, Rochester MN

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Abstract

Project Summary Epicardium is a mesothelium layer that covers the surface of a vertebrate heart. Epicardial activation, which is reflected by increased expression of certain epicardial genes in the whole epicardium, has been reported to play a vital role during heart regeneration. However, whether epicardial activation occurs in cardiac aging or cardiac diseases such as cardiomyopathies remains unknown. Using a zebrafish bag3 cardiomyopathy model, we recently noted accelerated cardiac aging in this cardiomyopathy model, and discovered fatty acid binding protein 7 (fabp7) as a therapeutic modifier gene. Interesting, Fabp7 manifests remarkable activation in the epicardium in the bag3 cardiomyopathy model, prompting that epicardial activation and associated remodeling an important pathological event. We went on to screen for aging-associated genes and identified gpnmb, a seno-surface marker, as another therapeutic modifier. Different from fabp7 that is activated in epithelial epicardium, gpnmb is activated in mesenchymal epicardium, a different epicardial subset. Consistent with the hypothesis that epicardial remodeling is an aging-associated event, we noted epicardial remodeling during normative cardiac aging in killifish and mouse. Together, these preliminary data prompted us to propose the central hypothesis predicting that epicardial remodeling is a pivotal pathological event in bag3 DCM and cardiac aging, which can be harnessed to mitigate cardiomyopathy and to rejuvenate an aged heart. Our proposal will be divided into the following three specific aims. In specific Aim 1, we focus on fabp7 and propose to test hypothesis that activation of fabp7 in epithelial epicardium represents a pathological event in bag3 DCM that can be inhibited to exert cardioprotective effects. In our Specific Aim 2, we propose to study gpnmb as a mesenchymal epicardial marker for epicardial remodeling. Its relationship with fabp7 in epithelial epicardium will be deciphered by promoter analysis, lineage tracing and genetic interaction studies. In Specific Aim 3, we propose to directly test the hypothesis that epicardial remodeling is a hallmark of normative cardiac aging. To facilitate genetic studies of cardiac aging, we will integrate African turquois killifish, a vertebrate model with the shortest lifespan, into our study. Once successful, the proposed experiments would significantly advance cardiomyopathy and cardiac aging fields by establishing epicardial remodeling as a novel pathological event in bag3 DCM, as well as a hallmark for normative cardiac aging.