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.

抽象的 肥胖会影响美国三分之一的成年人，是高血压发展的主要危险因素，这是领先的 全球心血管疾病和死亡的原因。肥胖占基本情况的70％ 高血压，管理与肥胖相关高血压的机制尚未解决。目前有 没有抗高血压药物旨在专门治疗肥胖患者的高血压，并针对治疗 迫切需要治疗这种高危人群。研究还将肥胖与大动脉僵硬相关， 心血管事件的独立预测指标，似乎是高血压发展的。 该应用的目的是阐明肥胖增加动脉刚度和的机制 血压。临床和实验证据表明，周围的脂肪被称为周围的动脉 脂肪组织（PVAT）和过氧化物组增殖物激活的受体伽马（PPARγ）在生理上具有 对血管系统的保护作用。我们的初步数据表明，西方饮食引起的肥胖小鼠 暴露的主动脉僵硬和高血压，伴随着PPARγ的高乙酰化 PVAT。此外，在血清和胸腔中，Asprosin的水平是一种新发现的脂肪因子 肥胖小鼠的主动脉和肠系膜PVAT。我们在肠系膜动脉中的初步功能数据表明 asprosin电位血管收缩并损害血管舒张，表明asprosin在 血管功能。令人惊讶的是，在我们的小鼠中降低了主动脉僵硬，以模仿PPARγ 脱乙酰化（称为2kR小鼠）喂食西方饮食。我们的中心假设是PPARγ高乙酰化 - 脂肪组织中的asprosin途径有助于与肥胖相关的主动脉僵硬和高血压。那，PPARγ 预计将脱乙酰化可以预防由肥胖引起的血管疾病。总体目标 这项工作是提供严格的科学证据，以支持PPARγ的治疗益处 患有高血压的肥胖患者的脱乙酰化。为了解决我们的假设，两个目标是 提议：（目标1）研究2kr小鼠是否受到肥胖诱导的主动脉僵硬度和 高血压。目的2）确定asprosin是否在PPARγ高乙酰化下游并研究其作用 关于血管功能。我们将使用西方饮食诱导的肥胖症和2kR小鼠的小鼠模型。在体内，ex vivo 并将聘请体外方法与药物和遗传方法结合使用以研究 PPARγ脱乙酰化和芦被素对血管功能的影响。成功完成该项目 将提供有关PPARγ乙酰化 - 杂素途径机制的新见解，这有助于我们 了解与肥胖相关的高血压和主动脉僵硬度 潜在的新治疗靶点用于治疗高血压。 REAP对这项建议的支持将促进 NYIT的创新研究环境，增强了科学的多样性，并为我们的 学生参加可能改变患者护理过程的临床相关研究。