Role of CHF1 in Occlusive Vascular Disease

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DESCRIPTION (provided by applicant): The transition of vascular smooth muscle cells from a differentiated, contractile to a proliferative, migratory and synthetic phenotype is hypothesized to be important in the development of occlusive vascular lesions. The genetic switches that regulate this phenotypic transition are not completely understood. We have previously identified CHF1, a bHLH transcription factor expressed in the cardiovascular system, as an important regulator of ventricular septation and function. We hypothesize that this protein is also a critical regulator of vascular smooth muscle cell (VSMC) function in the development of vascular disease. Our preliminary data from CHF1 knockout mice support this hypothesis, in that these mice show decreased neointimal formation after vascular injury, and that VSMCs from these mice show decreased migration in response to platelet derived growth factor (PDGF) and heparin binding epidermal growth factor (HB-EGF). The molecular defect at least partially involves attenuation of Racl activation. Our specific aims are: Aim 1: Characterize the molecular phenotype of VSMCs lacking CHF1 and determine the basis for decreased responsiveness to growth factors We will measure expression and activation of known components of the PDGF and HB-EGF signaling pathways, focusing initially on regulators of Racl activity. We will also perform a genomic analysis of wild type and knockout cells at varying time points after PDGF stimulation. Aim 2: Generate conditional CHF1 KO mice lacking CHF1 specifically in vascular smooth muscle. At present, it is unclear whether decreased neointima after injury in CHF1 KO mice is due to effects on local vascular smooth muscle, endothelium, circulating stem cells, or through a combination of cell types. To address this question, we will generate conditional knockout mice that lack CHF1 specifically in the smooth muscle layer of the vessel wall and then assess their response to vascular injury. Aim 3: Measure the effect of vascular smooth muscle cell CHF1 deficiency on experimental atherosclerosis. We hypothesize that CHFl-mediated effects on vascular smooth muscle are essential for the development of atherosclerotic lesions. We will cross conditional knockout mice lacking CHF1 in vascular smooth muscle with ApoE null mice and measure the development of atherosclerotic lesions in the double knockout mice.