AKAP150-TRPV4 regulation of endothelial function in obesity

AKAP150-TRPV4 对肥胖内皮功能的调节

• 批准号: 10424433
• 负责人: Swapnil K. Sonkusare
• 金额: $ 47.69万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424433
• 关键词: A kinase anchoring protein; Acetylcholine; Address; Adult; Affect; Arteries; Attenuated; Blood Pressure; Blood Vessels; Bradykinin; Cardiovascular Abnormalities; Cardiovascular Diseases; Coupled; Data; Development; Disease; Endothelial Cells; Endothelium; Event; Foundations; G alpha q Protein; Heart Diseases; High Fat Diet; Hypertension; Impairment; Individual; Knockout Mice; Knowledge; Mediating; Mesenteric Arteries; Molecular; Mus; NADPH Oxidase; Nerve; Obese Mice; Obesity; Pathologic; Peptides; Peroxonitrite; Pharmacology; Physiological; Play; Protein Kinase C; Proteins; Receptor Signaling; Regulation; Resistance; Rest; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Stroke; Testing; Therapeutic; Therapeutic Intervention; Vanilloid; Vascular Diseases; Vasodilation; base; blood pressure elevation; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; design; diet-induced obesity; endothelial dysfunction; improved; inhibitor; insight; new therapeutic target; novel therapeutic intervention; receptor; tool

Abstract. More than one-third of U.S. adults suffer from obesity, which is also an underlying risk factor for cardiovascular disorders including hypertension, stroke, and heart disease. It is, therefore, extremely important to understand how obesity promotes the development of these disorders. Obesity-induced endothelial dysfunction plays a crucial role in the development of cardiovascular abnormalities. In this application, we propose to address a major gap in the knowledge about pathological mechanisms for obesity-induced endothelial dysfunction. In resistance-sized arteries, endothelial Ca2+ signaling mechanisms regulate endothelium-dependent vasodilation. However, endothelial Ca2+ signaling mechanisms remain unexplored in obesity. We recently showed that Ca2+ influx through individual TRPV4 (transient receptor potential vanilloid 4) channels promotes endothelium- dependent vasodilation. Moreover, A kinase anchoring protein 150 (AKAP150), which can anchor protein kinase A and protein kinase C, is a key regulator of TRPV4 channel activity in the endothelium. We postulate that obesity-induced endothelial dysfunction reflects an impairment of AKAP150-TRPV4 channel regulation of endothelial function. Our preliminary data demonstrate that TRPV4 channel function and endothelium-dependent vasodilation are impaired, and blood pressure is elevated in high-fat diet-fed obese mice. Interestingly, TRPV4 channel function and TRPV4-mediated vasodilation were restored by peroxynitrite inhibitors, implicating a major role for peroxynitrite in obesity-induced endothelial dysfunction. Peroxynitrite has been previously implicated in vascular disorders, however, the molecular mechanisms for peroxynitrite-induced alteration of endothelial function are not known. Our data support the concept that peroxynitrite targets endothelial AKAP150 to lower TRPV4 channel activity. Therefore, we propose to test the hypothesis that peroxynitrite-induced impairment of AKAP150-TRPV4 regulation of endothelial function contributes to obesity-induced hypertension. In Specific Aim 1, we will test the hypothesis that AKAP150-TRPV4 channel regulation of endothelial Ca2+ signaling is impaired in obesity. We will also determine whether endothelium-specific deletion of AKAP150 or TRPV4 channels elevates resting blood pressure. In Specific Aim 2, we will determine how peroxynitrite impairs AKAP150-TRPV4 regulation of endothelial function, and test the hypothesis that elevated peroxynitrite levels disrupt AKAP150- TRPV4 regulation of endothelial function in obesity. These studies will identify new pathological mechanisms for and novel therapeutic strategies against cardiovascular abnormalities in obesity.

抽象的。 超过三分之一的美国成年人患有肥胖症，这也是心血管疾病的潜在危险因素 疾病包括高血压、中风和心脏病。因此，了解这一点极其重要 肥胖如何促进这些疾病的发展。肥胖引起的内皮功能障碍起着重要作用 在心血管异常的发展中发挥着至关重要的作用。在此应用中，我们建议解决一个 关于肥胖引起的内皮功能障碍的病理机制的认识存在重大差距。在 阻力大小的动脉，内皮 Ca2+ 信号传导机制调节内皮依赖性血管舒张。 然而，肥胖中的内皮 Ca2+ 信号传导机制尚未被探索。我们最近表明 Ca2+ 通过单个 TRPV4（瞬时受体电位香草酸 4）通道的流入促进内皮细胞 依赖性血管舒张。此外，激酶锚定蛋白150（AKAP150），可以锚定蛋白激酶 A 和蛋白激酶 C 是内皮细胞 TRPV4 通道活性的关键调节因子。我们假设 肥胖引起的内皮功能障碍反映了 AKAP150-TRPV4 通道调节的受损 内皮功能。我们的初步数据表明 TRPV4 通道功能和内皮依赖性 高脂肪饮食喂养的肥胖小鼠的血管舒张功能受损，血压升高。有趣的是，TRPV4 过氧亚硝酸盐抑制剂可恢复通道功能和 TRPV4 介导的血管舒张，这表明主要 过氧亚硝酸盐在肥胖引起的内皮功能障碍中的作用。过氧亚硝酸盐此前曾被认为 然而，血管疾病中过氧亚硝酸盐诱导的内皮细胞改变的分子机制 功能未知。我们的数据支持过氧亚硝酸盐针对内皮 AKAP150 降低的概念 TRPV4 通道活动。因此，我们建议检验过氧亚硝酸盐引起的损伤的假设 AKAP150-TRPV4 对内皮功能的调节有助于肥胖诱发的高血压。特定目标 1、我们将检验AKAP150-TRPV4通道对内皮Ca2+信号传导的调节受损的假设 在肥胖中。我们还将确定 AKAP150 或 TRPV4 通道是否是内皮特异性缺失 提高静息血压。在具体目标 2 中，我们将确定过氧亚硝酸盐如何损害 AKAP150-TRPV4 内皮功能的调节，并检验过氧亚硝酸盐水平升高会破坏 AKAP150- 的假设 TRPV4 对肥胖中内皮功能的调节。这些研究将确定新的病理机制 以及针对肥胖症心血管异常的新治疗策略。