Brayden Raper

Introduction: Heart disease is the leading cause of death in the United States. Atherosclerosis, a form of heart disease, is the build-up of plaque within blood vessels due to elevated levels of cholesterol and Low Density Lipoprotein (LDL). As levels of LDL increase within the artery and plaques begin to grow, there is a change in the flow within the vessel which plays an important role in inducing further formation of atherosclerotic plaques.⁶ The disturbed flow that triggers mechanosensitive proteins is generated in the inner wall of the curves; high levels of wall shear stress were found at the areas of stenosis. Cells within an atherosclerotic plaque have different properties than they do within the rest of the body, and these properties can be targeted through genetic therapy through mechanosensitive transcription factors (MSTFs).⁸ Methods: By identifying which of these factors are controlled through mechanosensitive pathways, drug therapy may be an option in the future to control and treat atherosclerosis. Apolipoprotein E (APOE) -/- mice were generated to carry CCN1 mutations along with apolipoprotein deficiency.⁷ In these mice, 3 of 4 branches of the Left Coronary Artery (LCA) were ligated, with the Right Coronary Artery (RCA) left as a control. Mouse aortic endothelial cells were isolated, seeded and put under several types of flow to induce mechanical stress. Other similar experiments were tested using different MSTFs, such as KLF4, Piezo1, and G_q/G_11.⁹ Results: CCN1 expression was upregulated after the ligation of the LCA branches within the mice, and the expression intensified after the beginning of structural changes due to the atherosclerotic plaques.⁷ Piezo1 and G_q / G₁₁ both were found to be significant in the inflammation process during disturbed flow.⁹ Currently, there is a genetic therapy using the monoclonal antibody Evinacumab to target ANGLPTL3 in volunteers with high levels of LDL.¹⁰ Conclusion: Downregulating these specific proteins yielded a direct decrease in the MSTF activated inflammation and plaque build-up. Through genetic therapies targeting these MSTFs using similar mechanisms as Evinacumab, there is an opportunity to not only treat atherosclerosis but to prevent it as well.

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