Targeting senescnt VSMCs in Atherosclerosis

靶向动脉粥样硬化中的衰老 VSMC

• 批准号: 10251681
• 负责人: Myriam Gorospe
• 金额: $ 11.23万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10251681
• 关键词: Age; Aging; Angiogenic Factor; Animal Model; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood flow; CCL2 gene; Cause of Death; Cell Adhesion Molecules; Cells; Chronic; Clinic; Complication; Cultured Cells; Development; Diabetes Mellitus; Dipeptidyl Peptidases; Disease; Disease Progression; Drug usage; Elderly; Exhibits; Exposure to; Galactosidase; Genetic; Growth; Human; IL8 gene; Incidence; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Interleukin-1; Interleukin-6; Intervention; Macaca mulatta; Modeling; Molecular; Monkeys; Mus; Myopathy; Obesity; Pharmaceutical Preparations; Phenotype; Population; Prevalence; Production; Proliferating; Risk Factors; Role; Rupture; Serum; Smoking; Smooth Muscle Myocytes; Stimulus; Structure; Sum; Surface; Time; Unhealthy Diet; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Smooth Muscle; age related; artery occlusion; atherosclerotic plaque rupture; chemokine; cytokine; glucose metabolism; inhibitor/antagonist; mortality; protein biomarkers; senescence

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.

动脉粥样硬化是随着时间的流逝的牙菌斑和动脉硬化的堆积，是老年人普遍存在的使人衰弱的疾病。 许多危险因素有助于动脉粥样硬化的发展，包括不健康的饮食，吸烟，遗传学，糖尿病，衰老和肥胖。 其中，衰老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。 与动脉粥样硬化有关的最严重的并发症和死亡原因是动脉的血栓性阻塞或因帽结构削弱引起的动脉粥样硬化斑块的侵蚀或破裂。该瓶盖由已推导成通常会增殖和迁移的合成的非收缩细胞的血管平滑肌细胞（VSMC）组成，以及少数衰老的VSMC。 动脉粥样硬化病变的衰老标志物SA-GAL（与衰老相关 - 乳糖苷酶）健康VSMC的水平升高。 此外，从高级动脉粥样硬化斑块中培养的VSMC还表现出其他衰老迹象，包括较长的人口倍增时间，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性炎症有关。 但是，尚不清楚VSMC的衰老，炎症和衰老之间的相互作用。 衰老细胞表现出与衰老相关的分泌表型（SASP），其中包括生产许多促炎细胞因子（例如IL-6，IL-8和IL-1）以及趋化因子（例如CCL2），粘附分子，粘附分子（例如，ICAM-1）（例如，ICAM-1）和Angig fest（E.G.，veff）。最近，我们确定了在衰老细胞表面上高表达的二肽基肽酶4（DPP4）。尽管尚不清楚DPP4对VSMC的影响，但在临床中使用了DPP4抑制剂，例如vildagliptin和其他Gliptin药物来治疗糖尿病。 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，与DPP4在葡萄糖代谢中的规范作用无关。 因此，我们建议通过追求这些目标来调查衰老VSMC中的DPP4： 目标1：我们正在调节暴露于动脉粥样硬化刺激的HVSMC中的DPP4表达水平，以确定DPP4对HVSMC衰老的影响。 目标2。我们正在用DPP4抑制剂和鼻溶剂治疗衰老的HVSMC，以确定对衰老进展的影响。 目标3。我们正在研究DPP4在动脉粥样硬化和动脉粥样硬化模型中血管疾病发展中的作用。