2. Investigating the Role of MIA3 in Human Aortic Smooth Muscle Cell Phenotypes Relevant to Atherosclerosis

Coronary artery disease (CAD) caused by atherosclerosis is the leading cause of death worldwide. This disease is characterized by the buildup of atherosclerotic plaque made of substances including lipids and cellular waste. Succeeding plaque buildup, Smooth Muscle Cells (SMCs) migrate and proliferate to form a fibrous cap that stabilizes the plaque. In severe cases, the fibrous cap may be unable to prevent plaque rupture which can cause a stroke or myocardial infarction. Genome-wide association studies (GWAS) have identified 163 independent loci that influence CAD risk, each with distinct pathogenesis pathways. 1q41, an independent locus harbors the gene Melanoma Inhibitory Activity 3 (MIA3). Recent studies have found that genetic variant(s) in this locus affects the gene expression of MIA3 in the vessel wall where the disease develops. Using a unique source of Human Aortic SMCs in our laboratory, we identified that the same genetic variant(s) from the 1q41 locus affects SMC migration and proliferation. In addition, our preliminary studies in human and mouse models have shown a relationship between increased MIA3 expression and stability of atherosclerotic fibrous cap. Few studies have addressed the mechanisms by which MIA3 contributes to CAD. Therefore, we hypothesize that MIA3 plays a beneficial role in plaque stability by influencing SMC migration and proliferation. We will test this hypothesis by downregulating and overexpressing MIA3 in human aortic SMC’s using CRISPR interference and activation respectively and quantifying migration and proliferation. Understanding the mechanisms of MIA3 will lead us closer to discovering therapeutic approaches to reduce CAD risk.