AKAP150-TRPV4 regulation of endothelial function in obesity

AKAP150-TRPV4 对肥胖内皮功能的调节

• 批准号: 10630829
• 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/10630829
• 关键词: A kinase anchoring protein; Acetylcholine; Address; Adult; Affect; Arteries; Attenuated; Blood Pressure; 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; Physiological; Play; Protein Kinase C; Receptor Signaling; Regulation; Resistance; Rest; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Stroke; Testing; Therapeutic; Therapeutic Intervention; Vanilloid; Vascular Diseases; Vasodilation; 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; pharmacologic; receptor; shear stress; 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，这也是心血管的潜在危险因素 包括高血压，中风和心脏病在内的疾病。因此，理解非常重要 肥胖如何促进这些疾病的发展。肥胖引起的内皮功能障碍播放 在心血管异常发展中的关键作用。在此应用程序中，我们建议解决 关于肥胖引起的内皮功能障碍的病理机制知识的主要差距。在 电阻大小的动脉，内皮Ca2+信号传导机制调节内皮依赖性血管舒张。 但是，内皮Ca2+信号传导机制在肥胖症中仍未探索。我们最近表明CA2+ 通过单个TRPV4（瞬态受体电位香草素4）通道涌入可促进内皮 - 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是内皮中TRPV4通道活性的关键调节剂。我们假设 肥胖引起的内皮功能障碍反映了AKAP150-TRPV4通道调节的损害 内皮功能。我们的初步数据表明TRPV4通道功能和内皮依赖性 血管舒张受损，并且在高脂饮食喂养的肥胖小鼠中血压升高。有趣的是，TRPV4 通道功能和TRPV4介导的血管舒张通过过氧亚硝酸盐抑制剂恢复，这意味着主要 过氧亚硝酸盐在肥胖引起的内皮功能障碍中的作用。过氧亚硝酸盐以前与 然而，血管疾病是过氧亚硝酸盐诱导的内皮改变的分子机制 功能尚不清楚。我们的数据支持过氧亚硝酸盐靶向内皮AKAP150的概念 TRPV4通道活动。因此，我们建议检验过氧亚硝酸盐诱导的损害的假设 AKAP150-TRPV4内皮功能的调节有助于肥胖引起的高血压。在特定目标中 1，我们将检验以下假设：内皮CA2+信号的AKAP150-TRPV4通道调节受损 肥胖。我们还将确定AKAP150或TRPV4通道的内皮特异性缺失是 升高静止的血压。在特定目标2中，我们将确定过氧亚硝酸盐如何损害AKAP150-TRPV4 调节内皮功能，并检验假设过高的过氧亚硝酸盐水平破坏AKAP150- TRPV4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型治疗策略。

项目成果

Role of TRP ion channels in cerebral circulation and neurovascular communication.

• DOI: 10.1016/j.neulet.2021.136258
• 发表时间: 2021-11-20
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Kuppusamy M;Ottolini M;Sonkusare SK
• 通讯作者: Sonkusare SK

Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1.

• DOI: 10.1172/jci.insight.165715
• 发表时间: 2023-05-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Ruddiman, Claire A.;Peckham, Richard;Luse, Melissa A.;Chen, Yen-Lin;Kuppusamy, Maniselvan;Corliss, Bruce A.;Hall, P. Jordan;Lin, Chien-Jung;Peirce, Shayn M.;Sonkusare, Swapnil K.;Mecham, Robert P.;Wagenseil, Jessica E.;Isakson, Brant E.
• 通讯作者: Isakson, Brant E.

Calcium Signal Profiles in Vascular Endothelium from Cdh5-GCaMP8 and Cx40-GCaMP2 Mice.

• DOI: 10.1159/000514210
• 发表时间: 2021
• 期刊: Journal of vascular research
• 影响因子: 1.7
• 作者: Chen YL;Baker TM;Lee F;Shui B;Lee JC;Tvrdik P;Kotlikoff MI;Sonkusare SK
• 通讯作者: Sonkusare SK