Obesity-related hypertension: the contribution of PPAR gamma acetylation and asprosin

肥胖相关高血压：PPAR γ 乙酰化和白脂素的贡献

• 批准号: 10654210
• 负责人: Maria Alicia Carrillo-Sepulveda
• 金额: $ 42.84万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654210
• 关键词: Acetylation; Address; Adipose tissue; Adult; Affect; Antihypertensive Agents; Aorta; Arginine; Arteries; Award; Biochemical; Blood Pressure; Blood Pressure Monitors; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Chest; Clinical; Data; Deacetylation; Development; Drug Design; Educational process of instructing; Endothelium; Environment; Epidemic; Essential Hypertension; Event; Exhibits; Exposure to; Fatty acid glycerol esters; Framingham Heart Study; Functional disorder; Genetic Engineering; Genetically Engineered Mouse; Goals; Histology; Human; Hypertension; Impairment; In Vitro; Institution; Knock-in Mouse; Life; Link; Lysine; Measurement; Medical Students; Mesenteric Arteries; Mesentery; Molecular; Mus; Mutation; Obese Mice; Obesity; Obesity Related Hypertension; Overweight; PPAR gamma; Pathway interactions; Patient Care; Phenotype; Physiologic pulse; Physiological; Play; Populations at Risk; Post-Translational Protein Processing; Proteins; Research; Resolution; Risk Factors; Role; Science; Serum; Smooth Muscle Myocytes; Students; System; Testing; Therapeutic; Thoracic aorta; Training; Vascular Diseases; Vascular Smooth Muscle; Vascular System; Vasodilation; Work; adipokines; arterial stiffness; blood pressure elevation; cardiovascular risk factor; clinically relevant; clinically significant; diet-induced obesity; experience; genetic approach; hypertension treatment; in vivo; innovation; insight; microCT; mimetics; mouse model; new therapeutic target; novel; obese patients; obesity treatment; pharmacologic; pre-clinical research; prevent; protective effect; sugar; targeted treatment; ultrasound; undergraduate student; vasoconstriction; western diet

Abstract Obesity affects 1 in 3 adults in the US and is a major risk factor for the development of hypertension, a leading cause of cardiovascular disease and death worldwide. While obesity accounts for 70% of cases of essential hypertension, the mechanisms governing obesity-related hypertension remain unresolved. Currently there are no anti-hypertensive drugs designed to treat hypertension specifically in obese patients and targeted therapy to treat this at-risk population is urgently needed. Studies have also associated obesity to stiffening of large arteries, an independent predictor for cardiovascular events that appears to precede the development of hypertension. The goal of this application is to elucidate the mechanism(s) by which obesity increases arterial stiffness and blood pressure. Clinical and experimental evidence shows that the fat surrounding arteries, termed perivascular adipose tissue (PVAT), and peroxisome proliferator-activated receptor gamma (PPARγ) possess physiologically protective effects on the vascular system. Our preliminary data shows that western diet-induced obese mice exhibited aortic stiffness and high blood pressure, which was accompanied by hyperacetylation of PPARγ in PVAT. Furthermore, levels of asprosin, a newly discovered adipokine, is increased in the serum and thoracic aorta and mesenteric PVAT from obese mice. Our preliminary functional data in mesenteric arteries reveal that asprosin potentiates vasoconstriction and impairs vasodilation, indicating a direct effect of asprosin in the vascular function. Strikingly, aortic stiffness was mitigated in our mice genetically engineered to mimic PPARγ deacetylation (called 2KR mice) fed a western diet. Our central hypothesis is that the PPARγ hyperacetylation- asprosin pathway in adipose tissue contributes to obesity-related aortic stiffness and hypertension. Thus, PPARγ deacetylation would be expected to protect against vascular disorders caused by obesity. The overarching goal of this work is to provide rigorous scientific evidence to support a therapeutic benefit of PPARγ deacetylation in obese patients suffering from hypertension. To address our hypothesis, two aims are proposed: (Aim 1) study whether 2KR mice are protected against obesity-induced aortic stiffness and hypertension. Aim 2) determine whether asprosin is downstream to PPARγ hyperacetylation and study its effects on vascular function. We will use a mice model of western diet-induced obesity and 2KR mice. In vivo, ex vivo and in vitro approaches in combination with pharmacological and genetic approaches will be employed to study the effects of PPARγ deacetylation and asprosin in vascular functionality. Successful completion of this project will provide novel insights into the mechanisms of the PPARγ acetylation-asprosin pathway, contribute to our understanding of obesity-related hypertension and aortic stiffness, and identify PPARγ deacetylation as a potential new therapeutic target for the treatment of hypertension. Support of this proposal by REAP will promote an innovative research environment at NYIT, enhance diversity in science and provide opportunities for our students to participate in clinically relevant research that may change the course of patient care.

摘要 在美国，肥胖影响着三分之一的成年人，是患高血压的主要危险因素，高血压是一种主要的 世界范围内心血管疾病和死亡的原因。而肥胖症占基础疾病病例的70% 高血压，肥胖相关高血压的调控机制仍未解决。目前有 没有专门用于治疗肥胖患者高血压的降压药物和靶向治疗 迫切需要治疗这些高危人群。研究还将肥胖与大动脉硬化联系起来， 一种心血管事件的独立预测因子，似乎先于高血压的发展。 本应用的目的是阐明肥胖增加动脉僵硬和动脉硬化的机制(S)。 血压。临床和实验证据表明，动脉周围的脂肪，称为血管周围 脂肪组织(PVAT)和过氧化物酶体增殖物激活受体γ(PPARγ)具有生理活性 对血管系统的保护作用。我们的初步数据显示，西方饮食诱导的肥胖小鼠 表现为主动脉僵硬和高血压，并伴有PPARγ的高乙酰化。 PVAT。此外，一种新发现的脂肪因子--天冬氨酸在血清和胸腔中的水平会增加。 肥胖小鼠的主动脉和肠系膜PVAT。我们肠系膜动脉的初步功能数据显示 阿司匹林增强血管收缩和损害血管扩张，表明阿司匹林直接作用于 血管功能。引人注目的是，我们通过基因工程模拟PPARγ的小鼠的主动脉僵硬程度得到了缓解 去乙酰化小鼠(称为2KR小鼠)喂食西方饮食。我们的中心假设是PPARγ的超乙酰化- 脂肪组织中的天冬氨酸途径与肥胖相关的主动脉僵硬和高血压有关。因此，PPARγ 去乙酰化有望预防肥胖引起的血管疾病。首要目标是 这项工作的目的是提供严格的科学证据来支持PPARγ的治疗益处 肥胖症高血压患者的去乙酰化。为了解决我们的假设，有两个目标 建议：(目的1)研究2KR小鼠是否对肥胖引起的主动脉僵硬和 高血压。目的2)确定天冬氨酸是否位于PPARγ高乙酰化下游，并研究其作用 关于血管功能的。我们将使用西方饮食诱导肥胖的小鼠模型和2KR小鼠。体内、体外 并将使用体外方法结合药理学和遗传学方法来研究 PPAR、γ脱乙酰化和Asprosin对血管功能的影响。本项目圆满完成 将为PPARγ乙酰化-天冬氨酸途径的机制提供新的见解，有助于我们的 了解肥胖相关高血压和主动脉僵硬，并确定PPARγ脱乙酰化是一种 治疗高血压的潜在新靶点。REAP对这项建议的支持将促进 NYIT的创新研究环境，增强科学的多样性，并为我们的 学生参与可能改变患者护理过程的临床相关研究。