Mechanisms for Ceramide Mediated Vascular Dysfunction

神经酰胺介导的血管功能障碍的机制

基本信息

批准号：
8366869
负责人：
John David SYMONS
金额：
$ 43.66万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8366869
关键词：
Academic Research Enhancement Awards Acute Address Adipose tissue Agonist Anabolism Animal Feed Arteries Attenuated Biological Availability Blood Pressure Blood Vessels Cardiovascular system Cause of Death Ceramides Characteristics Chronic Complex Complication Data Defect Dentistry Development Diabetes Mellitus Diet Discipline of Nursing Doctor of Philosophy Education Endothelial Cells Endothelium Enzymes Experimental Models Exposure to Fatty acid glycerol esters Fostering Functional disorder Gender Genetic Hypertension Impairment Individual Infusion procedures Insulin Resistance Laboratories Lead Link Lipids Liver Manuscripts Mediating Medicine Membrane Metabolic Mitogen-Activated Protein Kinase 3 Modeling Molecular Mus Nitric Oxide Nitric Oxide Synthase Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Palmitates Patients Peroxonitrite Pharmacy facility Phosphorylation Phosphotransferases Physical therapy Prevalence Production Protein phosphatase Repression Research Research Personnel Research Project Grants Risk Science Secondary to Signal Transduction Skeletal Muscle Sphingolipids Superoxides Testing Tissues Training United States United States National Institutes of Health Vascular Diseases Vasodilation age group ceramide-activated protein phosphatase clinically relevant design diabetic dihydroceramide desaturase dimer enzyme activity experience feeding human NOS3 protein in vivo insight novel prevent programs protein phosphatase 2A inhibitor 2 research study thermozymocidin

项目摘要

DESCRIPTION (provided by applicant): Patients with diet-induced obesity and type 2 diabetes are at greater risk for developing cardiovascular complications. An important complication is impaired blood vessel function. In a clinically relevant murine model of diet-induced obesity we showed that exposure to elevated free fatty acids (FFAs) reduces nitric oxide (NO) bioavailability leading to arterial dysfunction. My 2007 R15 sought to determine whether the signaling link between elevated FFAs and impaired NO bioavailability involves the lipid metabolite ceramide. Inhibition of ceramide synthesis with myriocin, or heterozygous deletion of dihydroceramide desaturase, an enzyme which catalyzes ceramide synthesis, prevented endothelial dysfunction and systemic hypertension, and preserved endothelial NO synthase (eNOS) phosphorylation in arteries from fat-fed mice. Molecular mechanisms whereby ceramide might lower NO bioavailability were examined using cultured endothelial cells. Palmitate induced repression of basal and agonist-stimulated eNOS phosphorylation, eNOS dimer formation, and NO production were restored following inhibition of ceramide synthesis. The ceramide-induced impairment of eNOS phosphorylation or dimer formation, respectively, was not the result of impaired kinase-mediated eNOS phosphorylation or superoxide anion-mediated peroxynitrite formation. [Instead, ceramide causes protein phosphatase 2A (PP2A) to associate directly with the eNOS/Akt complex, and this is concurrent with decreased basal and agonist-stimulated eNOS phosphorylation. New data obtained since the last submission suggest that PP2A attenuates eNOS phosphorylation by preventing phosphorylation of the pool of Akt that colocalizes with eNOS and / or by directly dephosphorylating eNOS.] In this renewal, Aim 1 will test the hypothesis that PP2A associates with and disrupts the Akt-Hsp90-eNOS complex as a consequence of de novo ceramide synthesis leading to impaired basal and agonist-stimulated eNOS phosphorylation. Aim 2 will test the hypothesis that ceramide relieves the association of inhibitor 2 of PP2A (I2PP2A) with PP2A such that PP2A can translocate to the membrane and associate with eNOS. Aim 3 will test the hypothesis that ceramide-induced, PP2A-mediated vascular dysfunction occurs in mice with diet-induced obesity. Results from these studies will provide mechanistic insight linking endogenous vascular ceramide biosynthesis to cardiovascular defects in a murine model of diet-induced obesity and type 2 diabetes, and present new targets for the treatment of vascular dysfunction in these prevalent conditions. Support for our research via the NIH R15 mechanism has provided > 35 undergraduate researchers with valuable experience and each has continued to pursue an advanced degree in the biomedical sciences. PUBLIC HEALTH RELEVANCE: Obesity can lead to type 2 diabetes and cardiovascular complications. Our research is focused on determining the mechanisms whereby obesity impairs blood vessel function. We will determine the mechanism whereby the fat metabolite ceramide impairs eNOS enzyme activity and precipitates arterial dysfunction.

描述（由申请人提供）：饮食引起的肥胖和 2 型糖尿病患者发生心血管并发症的风险更大。一个重要的并发症是血管功能受损。在饮食诱导肥胖的临床相关小鼠模型中，我们发现暴露于升高的游离脂肪酸（FFA）会降低一氧化氮（NO）的生物利用度，从而导致动脉功能障碍。我的 2007 R15 试图确定 FFA 升高和 NO 生物利用度受损之间的信号传导联系是否涉及脂质代谢物神经酰胺。用多球菌素抑制神经酰胺合成，或杂合删除二氢神经酰胺去饱和酶（一种催化神经酰胺合成的酶），可预防内皮功能障碍和全身性高血压，并保留脂肪喂养小鼠动脉中的内皮一氧化氮合酶 (eNOS) 磷酸化。使用培养的内皮细胞检查了神经酰胺可能降低 NO 生物利用度的分子机制。棕榈酸诱导的对基础和激动剂刺激的 eNOS 磷酸化、eNOS 二聚体形成和 NO 产生的抑制在神经酰胺合成受到抑制后得到恢复。神经酰胺诱导的 eNOS 磷酸化或二聚体形成受损，分别不是激酶介导的 eNOS 磷酸化或超氧阴离子介导的过氧亚硝酸盐形成受损的结果。 [相反，神经酰胺导致蛋白磷酸酶 2A (PP2A) 直接与 eNOS/Akt 复合物结合，这与基础和激动剂刺激的 eNOS 磷酸化减少同时发生。自上次提交以来获得的新数据表明，PP2A 通过阻止与 eNOS 共定位的 Akt 池的磷酸化和/或直接去磷酸化 eNOS 来减弱 eNOS 磷酸化。] 在本次更新中，目标 1 将测试 PP2A 关联并破坏的假设Akt-Hsp90-eNOS 复合物是神经酰胺从头合成的结果，导致基础和激动剂刺激受损eNOS 磷酸化。目标 2 将检验以下假设：神经酰胺可解除 PP2A 抑制剂 2 (I2PP2A) 与 PP2A 的关联，从而使 PP2A 可以易位至细胞膜并与 eNOS 关联。目标 3 将检验以下假设：神经酰胺诱导的、PP2A 介导的血管功能障碍发生在饮食诱导的肥胖小鼠中。这些研究的结果将提供内源性血管神经酰胺生物合成与饮食诱导肥胖和 2 型糖尿病小鼠模型中心血管缺陷之间联系的机制见解，并为治疗这些常见疾病中的血管功能障碍提供新的靶点。通过 NIH R15 机制对我们的研究的支持为超过 35 名本科研究人员提供了宝贵的经验，并且每个人都继续攻读生物医学科学的高级学位。公众健康相关性：肥胖可导致 2 型糖尿病和心血管并发症。我们的研究重点是确定肥胖损害血管功能的机制。我们将确定脂肪代谢物神经酰胺损害 eNOS 酶活性并导致动脉功能障碍的机制。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function.

由degs1表达缺陷介导的二氢神经酰胺/神经酰胺比率增加会损害脂肪细胞的分化和功能。

DOI：
发表时间：
2015-04
期刊：
影响因子：
7.7
作者：
Barbarroja, Nuria;Rodriguez;Nygren, Heli;Camargo, Antonio;Pirraco, Ana;Relat, Joana;Cuadrado, Irene;Pellegrinelli, Vanessa;Medina;Lopez;Tinahones, Francisco J;Symons, J David;Summers, Scott A;Oresic
通讯作者：
Oresic

Role of Endothelial Cells in Myocardial Ischemia-Reperfusion Injury.

内皮细胞在心肌缺血再灌注损伤中的作用。

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Singhal, Arun K;Symons, J David;Boudina, Sihem;Jaishy, Bharat;Shiu, Yan
通讯作者：
Shiu, Yan

Acute, quercetin-induced reductions in blood pressure in hypertensive individuals are not secondary to lower plasma angiotensin-converting enzyme activity or endothelin-1: nitric oxide.

高血压患者中槲皮素引起的急性血压降低并非继发于血浆血管紧张素转换酶活性或内皮素-1：一氧化氮降低。

DOI：
发表时间：
2012-08
期刊：
影响因子：
0
作者：
Larson, Abigail;Witman, Melissa A H;Guo, Yi;Ives, Stephen;Richardson, Russell S;Bruno, Richard S;Jalili, Thunder;Symons, J David
通讯作者：
Symons, J David

γ-Carboxyethyl hydroxychroman, a metabolite of γ-tocopherol, preserves nitric oxide bioavailability in endothelial cells challenged with high glucose.

γ-羧乙基羟基色满是γ-生育酚的代谢产物，可在受到高葡萄糖挑战的内皮细胞中保留一氧化氮的生物利用度。

DOI：
发表时间：
2016-12
期刊：
影响因子：
0
作者：
Li, Youyou;Bharath, Leena P;Qian, Ying;Ruan, Ting;Anandh Babu, Pon Velayutham;Bruno, Richard S;Symons, J David;Jalili, Thunder
通讯作者：
Jalili, Thunder

Opportunity "nox": a novel approach to preventing endothelial dysfunction in the context of insulin resistance.

机会“nox”：一种在胰岛素抵抗的情况下预防内皮功能障碍的新方法。