TRPC Channels in the Metabolic Syndrome

代谢综合征中的 TRPC 通道

• 批准号: 9066774
• 负责人: Alexander G. Obukhov
• 金额: $ 53.31万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066774
• 关键词: Adult; Aldosterone; American; Angiotensin II; Animal Model; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Biochemical; Biological; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cell Proliferation; Cell membrane; Central obesity; Cessation of life; Characteristics; Cholesterol; Complementary DNA; Coronary; Coronary Arteriosclerosis; Coronary artery; Development; Disease Progression; Dominant-Negative Mutation; Down-Regulation; Dyslipidemias; Electrophysiology (science); Electroporation; Exhibits; Experimental Designs; Family suidae; Fluorometry; Functional disorder; Gene Delivery; Glucose Intolerance; Goals; Histamine; Hormones; Human; Hypertension; Injury; Insulin Resistance; Ion Channel; Isometric Exercise; Lead; Measurement; Mediating; Metabolic syndrome; Microinjections; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Molecular; Myocardial Infarction; Obesity; Organ Culture Techniques; Outcome; Phosphotransferases; Plasma; Prevalence; Renin; Renin-Angiotensin-Aldosterone System; Research; Role; Sarcoplasmic Reticulum; Sclerosis; Severities; Signal Pathway; Signal Transduction; Site; Smooth Muscle Myocytes; Spironolactone; Stenosis; Surface; TRP channel; Techniques; Therapeutic Effect; Ultrasonography; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; Vasoconstrictor Agents; clinically significant; defined contribution; fasting glucose; fluorescence imaging; in vivo; inhibitor/antagonist; injured; migration; neointima formation; new therapeutic target; novel; novel strategies; oxidant stress; prevent; programs; receptor; receptor operated channel; response; small hairpin RNA; sound; targeted delivery; treatment strategy; voltage

DESCRIPTION (provided by applicant): Canonical TRP channels (TRPC) form store- and receptor-operated Ca2+-permeable channels in the plasma membrane of vascular smooth muscle cells. TRPCs have been implicated in regulating vascular tone and smooth muscle cell proliferation. This proposal will define the molecular roles of TRPC channels during coronary artery remodeling associated with metabolic syndrome (MetS). MetS is characterized by central obesity, elevated plasma cholesterol and fasting glucose, hypertension, insulin resistance, and atherosclerosis. The prevalence of MetS among adults in the USA is 24%. In this research program, we will utilize the MetS Ossabaw pig model that exhibits all of the characteristics of MetS, including the overactive renin-angiotensin- aldosterone system (RAAS). We demonstrated that the expression levels of TRPC1 and TRPC6 channels are markedly elevated in MetS Ossabaw pig coronary arteries exhibiting atherosclerosis and hypercontractility. Consistently, freshly isolated MetS coronary artery smooth muscle cells had elevated store-/receptor-operated Ca2+ influx and large store-/receptor-operated TRPC-like currents. Since angiotensin II and aldosterone are positive regulators of TRPC expression, we hypothesize that, in MetS, the overactive RAAS upregulates TRPC1 and TRPC6 expression, which drives increased coronary smooth muscle cell proliferation and coronary artery hypercontractility. The following Specific Aims will be pursued: 1) To determine how the molecular expression of TRPCs is altered during the MetS-associated remodeling of coronary artery smooth muscle cells; 2) To define the contribution of TRPCs to endogenous store- and receptor-activated Ca2+ influx/currents in control and MetS coronary artery smooth muscle cells; 3) To determine whether the functional expression of endogenous TRPC channels is directly regulated by RAAS components, angiotensin II and Aldo, in coronary artery smooth muscle cells; 4) To determine whether the in vivo, coronary artery targeted down- regulation of TRPCs slows atheroma progression and decreases coronary artery hypercontractility in MetS pigs. During this research program, we will use molecular biological, biochemical, electrophysiological, and fluorescence imaging approaches as well as intravascular ultrasound, isometric tension and coronary artery ring lumen area measurements. Additionally, a coronary artery targeted delivery approach will be employed to deploy shRNAs and cDNA constructs into the coronary artery wall in vivo. Importantly, we will determine the distinct roles of TRPC1 and TRPC6 during MetS-associated NATIVE atherosclerosis progression.

描述（由申请人提供）：在血管平滑肌细胞的质膜中，构成商店和受体操作的Ca2+可渗透通道形成储存的CA2+可渗透通道。 TRPC与调节血管张力和平滑肌细胞增殖有关。该建议将定义与代谢综合征（METS）相关的冠状动脉重塑期间TRPC通道的分子作用。 MetS的特征是中枢肥胖，血浆胆固醇和空腹葡萄糖，高血压，胰岛素抵抗和动脉粥样硬化。美国成年人中大都会的患病率为24％。在该研究计划中，我们将利用Mets Ossabaw Pig模型，该模型展示了MetS的所有特征，包括过度活跃的肾素 - 血管紧张素 - 醛固酮系统（RAAS）。我们证明，在表现出动脉粥样硬化和超收缩性的大都会大都会猪冠状动脉中，TRPC1和TRPC6通道的表达水平显着升高。一致地，新鲜分离的MetS冠状动脉平滑肌细胞具有升高的商店/受体操Ca2+流入和大型商店/受体/受体操的TRPC样电流。由于血管紧张素II和醛固酮是TRPC表达的阳性调节剂，因此我们假设在MetS中，过度活跃的RAA上调TRPC1和TRPC6表达，这会驱动冠状动脉平滑肌细胞增殖和冠状动脉超额划痕。将追求以下特定目标：1）确定在与MetS相关的冠状动脉平滑肌细胞重塑期间，TRPC的分子表达如何改变； 2）定义TRPC对对照和Mets冠状动脉平滑肌细胞中内源性存储和受体激活的Ca2+流入/电流的贡献； 3）确定内源性TRPC通道的功能表达是否受冠状动脉平滑肌细胞中的RAAS成分，血管紧张素II和Aldo的直接调节； 4）确定冠状动脉的体内冠状动脉是否针对TRPC的下调会减慢动脉瘤的进展并降低大都会猪的冠状动脉超收缩性。在此研究计划中，我们将使用分子生物学，生化，电生理和荧光成像方法以及血管内超声，等距张力和冠状动脉环形发光液面积测量。此外，将采用冠状动脉靶向输送方法将shrnas和cDNA构建体部署到体内冠状动脉壁中。重要的是，我们将在与MetS相关的天然动脉粥样硬化进展过程中确定TRPC1和TRPC6的不同作用。

项目成果

Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice.

• DOI: 10.1161/atvbaha.116.308561
• 发表时间: 2017-01
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Chen X;Qian S;Hoggatt A;Tang H;Hacker TA;Obukhov AG;Herring PB;Seye CI
• 通讯作者: Seye CI

Phenylephrine, a common cold remedy active ingredient, suppresses uterine contractions through cAMP signalling.

• DOI: 10.1038/s41598-018-30094-5
• 发表时间: 2018-08-03
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Chen X;Meroueh M;Mazur G;Rouse E;Hundal KS;Stamatkin CW;Obukhov AG
• 通讯作者: Obukhov AG