Chemerin stimulation of vascular function in support of blood pressure

凯莫瑞刺激血管功能以支持血压

• 批准号: 9761280
• 负责人: David Ferland
• 金额: $ 3.51万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2020-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761280
• 关键词: Address; Adipocytes; Adipose tissue; Animal Model; Antisense Oligonucleotides; Aorta; Apple; Arteries; Basic Science; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Categories; Cells; Chemotaxis; Chronic; Clinical; Comorbidity; Contracts; Data; Dendritic Cells; Development; Diagnosis; Disease; Dyslipidemias; Elements; Engineering; Epidemiology; Event; Fatty acid glycerol esters; Fibroblasts; Health; High Fat Diet; Human; Human Pathology; Hypertension; Immune; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Knowledge; Label; Literature; Liver; Mediator of activation protein; Mesentery; Metabolic Marker; Metabolic syndrome; Modeling; Natural Killer Cells; Obesity; Overweight; Pathologic; Pathology; Pear; Pharmacology; Physiological; Protein Isoforms; Proteins; Psoriasis; Rat Strains; Rattus; Recording of previous events; Research; Research Personnel; Resistance; Role; Smooth Muscle Myocytes; Sprague-Dawley Rats; Superior mesenteric artery structure; Travel; Vascular Smooth Muscle; Visceral; Visceral fat; Work; adipokines; base; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; chemokine; cohesion; cytokine; falls; high risk; human model; in vivo; knock-down; macrophage; male; mortality risk; novel; novel marker; obesity management; paracrine; response; vasoconstriction

Project Summary Chemerin is a protein with a wide array of clinical associations but its physiological role has yet to be defined. In the epidemiological literature, circulating chemerin protein levels are increased with BMI and blood pressure. Chemerin is also used as a novel marker for metabolic syndrome which incorporates the dyslipidemia of obesity with hypertension and other cardiovascular diseases. Work looking at the association of chemerin with immune cells concludes that chemerin is pro-inflammatory. This is congruent with the fact that chemerin is associated with the inflammatory pathologies of hypertension and obesity. Other work has been performed on chemerin’s interaction with adipocytes. Chemerin is adipogenic in a paracrine fashion – meaning that chemerin is secreted by adipocytes for local travel to other adipocytes. Our lab has previously studied the interactions of chemerin with the vasculature. Chemerin is able to stimulate the smooth muscle cells in the rat aorta, superior mesenteric artery, and mesenteric resistance vessel to contract. These mesenteric resistance vessels are important to the chronic vasoconstriction observed in hypertension but are also surrounded by a perivascular adipose tissue (PVAT) that expands in the setting of obesity. We believe that the paracrine release of chemerin from this PVAT is inducing a chronic vasoconstriction in the mesenteric resistance vessels that contributes to the high blood pressure observed in those who are obese. Knockdown of chemerin in the entire rat body by antisense oligonucleotide (ASO) causes a fall in blood pressure. In a rat who has increased blood pressure and adiposity, this fall is even more dramatic. In rats, the diagnosis of obesity is poorly defined. While our data will still correlate to the human condition of obesity-associated hypertension, we are only able to make conclusions in the rat with reference to adiposity-associated hypertension. We will address the hypothesis, adiposity-associated hypertension is promoted by the release of chemerin from mPVAT (primarily adipocytes), in two aims: 1) Knockdown of chemerin reduces blood pressure in adiposity-associated hypertensive rats vs. control rat models. This addresses the in vivo interactions of chemerin, fat, and blood pressure using ASOs and the high-fat DahlS model of adiposity-associated hypertension. 2) Chemerin secreted from mPVAT in response to inflammatory mediators causes vascular smooth muscle stimulation. This addresses the specific interactions between chemerin, mPVAT adipocytes, and the smooth muscle cells of the vasculature. These results will solidify chemerin’s role as a mediator between the adipocyte and vasculature and allow us to use it as a pharmacological target in the management of obesity-associated hypertension.

项目摘要 Chmerin是一种具有广泛临床关联性的蛋白质，但其生理作用尚未得到证实。 已定义。在流行病学文献中，循环趋化蛋白水平随着BMI和 血压。Chmerin也被用作代谢综合征的新标记物，它结合了 肥胖合并高血压和其他心血管疾病的血脂异常。工作时看着 趋化蛋白与免疫细胞的关系得出结论，趋化蛋白具有促炎作用。这是 与趋化蛋白与高血压的炎性病理有关的事实一致 还有肥胖症。关于趋化蛋白与脂肪细胞的相互作用也进行了其他研究。Chmerin是 以旁分泌的方式成脂--意味着趋化蛋白由脂肪细胞分泌，用于局部运输 其他脂肪细胞。我们的实验室以前曾研究过趋化蛋白与血管系统的相互作用。 Chmerin能刺激大鼠主动脉、肠系膜上动脉和 肠系膜阻力血管收缩。这些肠系膜阻力血管对 高血压患者存在慢性血管收缩，但也被血管周围脂肪包围 组织(PVAT)，在肥胖的背景下扩张。我们认为趋化蛋白的旁分泌释放 在肠系膜阻力血管中诱导慢性血管收缩， 导致肥胖者的高血压。细胞趋化蛋白基因敲除的研究进展 通过反义寡核苷酸(ASO)使大鼠全身血压下降。在一只老鼠身上 血压升高和肥胖，这一下降更加戏剧性。在大鼠身上，肥胖的诊断 定义不明确。虽然我们的数据仍将与与肥胖相关的人类状况相关 高血压，我们只能在大鼠中得出与肥胖相关的结论 高血压。我们将解决这一假设，肥胖相关高血压是由 从mPVAT(主要是脂肪细胞)释放趋化蛋白，有两个目的： 1)抑制趋化蛋白降低肥胖相关高血压大鼠的血压 与对照组大鼠模型比较。它解决了趋化蛋白、脂肪和血液在体内的相互作用 使用ASOS和肥胖相关高血压的高脂肪Dahls模型的压力。 2)mPVAT对炎症介质的反应分泌的Chmerin引起血管 平滑肌肉刺激。这解决了趋化蛋白、细胞趋化蛋白、 MPVAT脂肪细胞和血管系统的平滑肌细胞。 这些结果将巩固趋化蛋白在脂肪细胞和血管系统之间的中介作用，并允许 美国将其用作治疗肥胖相关高血压的药理靶点。