Molecular regulation of the myocardin factors in vascular smooth muscle

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DESCRIPTION (provided by applicant): Vascular smooth muscle cell (SMC) differentiation is a very important process during vasculogenesis and angiogenesis, and it is well recognized that alterations in SMC phenotype play a role in the progression of several prominent cardiovascular disease states including atherosclerosis, hypertension, and restenosis. The myocardin and the myocardin-related transcription factors (MRTFs) are extremely important regulators of SMC differentiation, and the identification of the mechanisms that regulate myocardin factor activity will be important for our understanding of SMC-specific transcription. We have identified the histone demethylase, jmjd1a, as a myocardin factor binding protein and our preliminary data indicate that the demethylation of histone 3 lysine 9 (H3K9) by jmjd1a regulates SMC-specific transcription. We also have preliminary data to suggest that myocardin factor stability is regulated by ubiquitin-mediated proteosomal degradation, and that the MURF family of E3 ligases and the LIM domain protein, FHL2, may regulate this pathway in SMC. The goal of the current proposal is to further characterize these novel mechanisms in the regulation of SMC phenotype. Our specific aims are as follows; 1) to evaluate the contributions of jmjd1a to the regulation of SMC phenotype. We will measure H3K9 methylation and acetylation at the SMC-specific promoters and knock-down jmjd1a expression to test its effects on SMC-specific gene expression and myocardin factor activity. We will examine jmjd1a knockout mice for defects in SMC differentiation during development and for alterations in SMC phenotypic modulation following vessel injury. 2) to study the role of proteosomal-mediated degradation of the myocardin factors on SMC phenotype. We will measure myocardin and MRTF ubiquitination in SMC, identify lysine residues that are ubiquitinylated, and determine the roles of individual MURF family E3 ligases and FHL2 on myocardin factor stability. We will also examine myocardin factor stability and SMC differentiation in Murf1 and Murf3 knockout mice. Completion of these aims should lead to a better understanding of the regulation of myocardin factor activity in SMC which could aid in the development of therapeutics designed to treat a number of cardiovascular diseases. PUBLIC HEALTH RELEVANCE: Vascular smooth muscle cell differentiation is a very important process during the development of blood vessels and it is well recognized that alterations in this process play a role in the progression of several prominent cardiovascular disease states including atherosclerosis, hypertension, and restenosis. Our proposal examines the molecular mechanisms that regulate smooth muscle differentiation and should help to identify therapeutic targets for the treatment of these diseases.