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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在美国，三分之一的成年人患有肥胖症，并且是患高血压的主要危险因素，而高血压是导致高血压的主要因素。肥胖是全球心血管疾病和死亡的主要原因。高血压，肥胖相关高血压的机制目前尚未解决。没有专门用于治疗肥胖患者高血压的抗高血压药物，也没有针对肥胖患者的靶向治疗研究还表明肥胖与大动脉硬化有关，迫切需要治疗这一高危人群。似乎先于高血压发生的心血管事件的独立预测因子。本申请的目的是阐明肥胖增加动脉僵硬度和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）在生理学上具有我们的初步数据表明，西方饮食引起的肥胖小鼠。表现出主动脉僵硬和高血压，并伴有 PPARγ 的过度乙酰化此外，血清和胸部的白脂素（一种新发现的脂肪因子）水平升高。我们对肠系膜动脉的初步功能数据表明，肥胖小鼠的主动脉和肠系膜 PVAT。白脂素增强血管收缩并损害血管舒张，表明白脂素对血管有直接作用。引人注目的是，经过基因改造模拟 PPARγ 的小鼠的主动脉僵硬度得到了缓解。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 过度乙酰化- 脂肪组织中的白脂素途径导致肥胖相关的主动脉僵硬和高血压。脱乙酰化有望预防肥胖引起的血管疾病。这项工作的目的是提供严格的科学证据来支持 PPARγ 的治疗益处患有高血压的肥胖患者的脱乙酰化为了解决我们的假设，有两个目标。提议：（目标 1）研究 2KR 小鼠是否能够预防肥胖引起的主动脉僵硬和目标 2) 确定白脂素是否是 PPARγ 过度乙酰化的下游并研究其影响。我们将使用西方饮食诱导的肥胖小鼠模型和 2KR 小鼠体内、离体模型。将采用体外方法结合药理学和遗传学方法进行研究 PPARγ 脱乙酰化和白脂素对血管功能的影响该项目成功完成。将为 PPARγ 乙酰化 - 白脂素途径的机制提供新的见解，有助于我们了解肥胖相关的高血压和主动脉僵硬，并将 PPARγ 脱乙酰化确定为 REAP 对这一提案的支持将促进高血压治疗的潜在新治疗靶点。纽约理工学院的创新研究环境，增强了科学的多样性，并为我们的学生提供了机会学生参与可能改变患者护理过程的临床相关研究。