Targeting senescnt VSMCs in Atherosclerosis

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Atherosclerosis, the buildup of plaque and hardening of the arteries over time, is a widespread and debilitating disease in the elderly. Many risk factors contribute to the development of atherosclerosis, including an unhealthy diets, smoking, genetics, diabetes, aging, and obesity. Among them, aging is one of the most important factors, increasing the prevalence, incidence, and mortality associated with atherosclerosis. The most serious complication and leading cause of death associated with atherosclerosis is the thrombotic occlusion of the arteries following erosion or rupture of an atherosclerotic plaque caused by weakening of the cap structure. The cap consists of vascular smooth muscle cells (VSMCs) that have dedifferentiated into synthetic, non-contractile cells that typically proliferate and migrate, and by a small population of senescent VSMCs. Atherosclerotic lesions have increased levels of the senescence marker SA-Gal (senescence-associated -galactosidase) healthy VSMCs. In addition, VSMCs cultured from advanced atherosclerotic plaques also exhibit other signs of senescence, including longer population doubling times, senescence marker proteins like p16, and growth arrest. The development of age-related multi-factorial diseases such as atherosclerosis is associated with persistent systemic inflammation. However, the interplay between aging, inflammation, and senescence of VSMCs is not well understood. Senescent cells exhibit a senescence-associated secretory phenotype (SASP) that includes production of many proinflammatory cytokines (e.g., IL-6, IL-8, and IL-1), as well as chemokines (e.g., CCL2), adhesion molecules (e.g., ICAM-1), and angiogenic factors (e.g., VEGF). Recently, we identified dipeptidyl peptidase 4 (DPP4) highly expressed on the surface of senescent cells. While the effect of DPP4 on VSMCs is not well understood, DPP4 inhibitors such as Vildagliptin and other gliptin drugs are used in the clinic to treat Diabetes. In animal models, they have shown the ability to reduce atherosclerosis and inflammation, independent of DPP4s canonical role in glucose metabolism. Thus, we propose to investigate DPP4 in senescent VSMCs by pursuing these objectives: Objective 1: We are modulating DPP4 expression levels in hVSMCs exposed to atherogenic stimuli to determine the impact of DPP4 on hVSMC senescence. Objective 2. We are treating senescent hVSMCs with DPP4 inhibitors and senolytic drugs to determine effects on the progression of senescence. Objective 3. We are studying the role DPP4 in the development of vascular disease in murine and rhesus monkey models of atherosclerosis.