Nitroalkenes and Blood Pressure Regulation

硝基烯烃和血压调节

• 批准号: 7466539
• 负责人: YUQING Eugene CHEN
• 金额: $ 37.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466539
• 关键词: 2,4-thiazolidinedione; Accounting; Acute; Adverse effects; Affinity; Agreement; Angiotensin II; Antidiabetic Drugs; Antihypertensive Agents; Antisense RNA; Atherosclerosis; Attenuated; Back; Binding; Bioinformatics; Biological Assay; Biological Models; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cessation of life; Complications of Diabetes Mellitus; Computer Simulation; Data; Development; Diabetes Mellitus; Diagnostic; Dominant-Negative Mutation; Dose; Down-Regulation; Drug Design; Dyslipidemias; Edema; Event; Exhibits; Extracellular Domain; Fibroblasts; Figs - dietary; GW9662; Gene Deletion; Gene Targeting; Goals; Hepatotoxicity; Histidine; Hour; Human; Hyperlipidemia; Hypertension; Hypotension; In Vitro; Individual; Insulin Resistance; Knock-out; Knowledge; Laboratories; Lead; Ligands; Link; Linoleic Acids; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic syndrome; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutate; Mutation; Nitrates; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oleic Acid; Oleic Acids; Oligonucleotides; PPAR gamma; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Play; Positioning Attribute; Property; Protein Overexpression; Proteins; Public Health; RNA Interference; Rattus; Reaction; Reactive Nitrogen Species; Receptor Down-Regulation; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin System; Reporting; Repression; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Structure; Testing; Therapeutic; Thiazolidinediones; Time; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Translational Regulation; Untranslated Regions; Vascular Diseases; Vascular remodeling; Weight Gain; Work; aqueous; authority; base; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; cell growth; clinically significant; defined contribution; design; drug development; genetic manipulation; hypertension treatment; in vitro Model; in vivo; insight; mortality; mouse model; mutant; nitrate; nitroalkene; non-diabetic; novel; novel therapeutics; protective effect; radioligand; receptor; research study; response; rosiglitazone; success; telmisartan; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): It has been well documented that cardiovascular complications of diabetes account for 75% of all deaths in patients with type 2 diabetes. Hypertension occurs approximately twice as frequently in patients with diabetes compared with non-diabetic individuals. Although it is clear that the state of diabetes confers an increased risk of cardiovascular events, the mechanism by which metabolic perturbations influence vascular function and structure remain to be further defined. Emerging data suggest that peroxisome proliferator-activated receptor-3 (PPAR3) and angiotensin II (Ang II) type 1 receptor (AT1R) are two critical determinants that may provide functional links between obesity/diabetes, hypertension and cardiovascular disease (CVD). Recently, we have reported the identification of nitroalkene derivatives of linoleic acid (LNO2) and oleic acid (OA-NO2) with concentrations exceeding 1 <M in the human circulation, as potent endogenous PPAR-gamma ligands. Intriguingly, our preliminary studies have demonstrated for the first time that nitroalkenes not only can block Ang II binding to AT1R, but also suppress the AT1R expression in vascular smooth muscle cells (VSMC). In addition, we have observed that exogenous administration of OA-NO2 decreases blood pressure in mice. Therefore, nitroalkenes may exert "vascular and metabolic protective" effects through a combination of down- regulation of the AT1R signaling pathway and activation of PPAR3-dependent protective events in VSMC. In this proposal, we will test the central hypothesis that nitroalkenes are novel endogenous molecules that regulate blood pressure and hypertensive vascular remodeling by activating antihypertensive and antidiabetic signaling pathways in VSMC. Specifically, we will: 1). Determine the molecular mechanisms of OA-NO2-inhibition of the AT1R signaling pathway; 2). Define the contributory roles of OA-NO2-mediated AT1R and PPAR3 signaling pathways in the regulation of VSMC proliferation; 3). Define the contributory roles of OA-NO2- mediated AT1R and PPAR3 signaling pathways in the regulation of blood pressure and hypertensive vascular remodeling. The successful implementation of these goals should lead to a better understanding of endogenous signaling actions of the model nitroalkene, OA-NO2, in the vasculature and will set strong basis for new perspectives on rational drug design and development of nitroalkene derivatives with antihypertensive and antidiabetic properties. Project Narrative: It has been well documented that cardiovascular complications of diabetes account for 75% of all deaths in patients with type 2 diabetes. Hypertension occurs approximately twice as frequently in patients with diabetes compared with non-diabetic individuals. Although it is clear that the state of diabetes confers an increased risk of cardiovascular events, the mechanism by which metabolic perturbations influence vascular function and structure remain to be further defined. The successful implementation of this proposal should lead to a better understanding of endogenous signaling actions of nitroalkenes in the vasculature and will set strong basis for new perspectives on rational drug design and development of nitroalkene derivatives with antihypertensive and antidiabetic properties.

描述(申请人提供)：有充分的文献记载，糖尿病的心血管并发症占2型糖尿病患者死亡总数的75%。与非糖尿病患者相比，糖尿病患者发生高血压的频率大约是非糖尿病患者的两倍。虽然糖尿病的状态明显增加了心血管事件的风险，但代谢紊乱影响血管功能和结构的机制仍有待进一步确定。研究表明，PPAR3和血管紧张素II(Ang II)1型受体(AT1R)是肥胖/糖尿病、高血压和心血管疾病(CVD)之间的两个重要决定因素。最近，我们报道了亚油酸和油酸的硝基烯烃衍生物(LNO2)和油酸(OA-NO2)在人体循环中的浓度超过1&lt；M，是有效的内源性PPAR-γ配体。有趣的是，我们的初步研究首次证明，硝基烯烃不仅可以阻断血管紧张素Ⅱ与AT1R的结合，而且还可以抑制血管平滑肌细胞(VSMC)AT1R的表达。此外，我们还观察到外源性给予OA-NO2可降低小鼠的血压。因此，硝基烯可能通过下调AT1R信号通路和激活依赖PPAR3的保护事件来发挥血管和代谢保护作用。在这个提案中，我们将检验中心假设，即硝基烯烃是一种新的内源性分子，通过激活VSMC中的降压和抗糖尿病信号通路来调节血压和高血压血管重构。具体来说，我们将：1)。确定OA-NO2抑制AT1R信号通路的分子机制；2)。明确OA-NO2介导的AT1R和PPAR3信号通路在VSMC增殖调控中的作用；明确OA-NO2介导的AT1R和PPAR3信号通路在调节血压和高血压血管重构中的作用。这些目标的成功实现将有助于更好地理解模型硝基烯烃(OA-NO2)在血管系统中的内源性信号作用，并将为合理设计和开发具有降压和降糖特性的硝基烯烃衍生物奠定坚实的基础。 项目简介：糖尿病的心血管并发症占2型糖尿病患者死亡总数的75%，已经有充分的文献记载。与非糖尿病患者相比，糖尿病患者发生高血压的频率大约是非糖尿病患者的两倍。虽然糖尿病的状态明显增加了心血管事件的风险，但代谢紊乱影响血管功能和结构的机制仍有待进一步确定。这一建议的成功实施将有助于更好地理解硝基烯类化合物在血管系统中的内源性信号传递作用，并将为合理设计和开发具有降压和降糖活性的硝基烯烃类化合物奠定坚实的基础。