Targeting senescnt VSMCs in Atherosclerosis

动脉粥样硬化，随着时间的推移斑块和动脉硬化的积累，是一种广泛存在的老年人衰弱的疾病。 许多危险因素导致动脉粥样硬化的发展，包括不健康的饮食、吸烟、遗传、糖尿病、衰老和肥胖。 其中，老龄化是最重要的因素之一，增加了与动脉粥样硬化相关的患病率、发病率和死亡率。 与动脉粥样硬化相关的最严重的并发症和主要的死亡原因是动脉粥样硬化斑块的侵蚀或破裂后的动脉血栓性闭塞，所述动脉粥样硬化斑块由冠状结构的弱化引起。帽由血管平滑肌细胞（VSMC）和少量衰老的VSMC组成，所述血管平滑肌细胞（VSMC）已去分化成通常增殖和迁移的合成的非收缩性细胞。 动脉粥样硬化病变增加了健康VSMC的衰老标志物SA-Gal（衰老相关半乳糖苷酶）水平。 此外，从晚期动脉粥样硬化斑块中培养的VSMC也表现出其他衰老迹象，包括更长的群体倍增时间，衰老标记蛋白如p16和生长停滞。 与年龄相关的多因素疾病如动脉粥样硬化的发展与持续的全身炎症有关。 然而，老化，炎症和VSMC衰老之间的相互作用还没有很好地理解。 衰老细胞表现出衰老相关分泌表型（SASP），其包括许多促炎细胞因子（例如，IL-6、IL-8和IL-1），以及趋化因子（例如，CCL 2），粘附分子（例如，ICAM-1）和血管生成因子（例如，VEGF）。最近，我们发现二肽基肽酶4（DPP 4）在衰老细胞表面高度表达。虽然DPP 4对VSMC的作用还不清楚，但DPP 4抑制剂如维达利和其他格列奈药物在临床上用于治疗糖尿病。 在动物模型中，它们显示出减少动脉粥样硬化和炎症的能力，而不依赖于DPP 4在葡萄糖代谢中的典型作用。 因此，我们建议通过追求这些目标来研究衰老VSMC中的DPP 4： 目的1：我们调节暴露于致动脉粥样硬化刺激的hVSMC中的DPP 4表达水平，以确定DPP 4对hVSMC衰老的影响。 目标2.我们正在用DPP 4抑制剂和衰老药物治疗衰老的hVSMC，以确定对衰老进展的影响。 目标3. 我们正在研究DPP 4在小鼠和恒河猴动脉粥样硬化模型中血管疾病发展中的作用。

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.