MECHANISMS OF VASCULAR WALL THICKENING OF AGED RATS

老年大鼠血管壁增厚的机制

• 批准号: 6287558
• 负责人: RAMESH C BHALLA
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287558
• 关键词: age difference; animal old age; atherosclerosis; biological signal transduction; cell migration; cell proliferation; enzyme induction /repression; gel mobility shift assay; hypertension; interleukin 1; laboratory rat; mature animal; metalloendopeptidases; mitogen activated protein kinase; nitric oxide; nitric oxide synthase; northern blottings; tissue /cell culture; transfection; vascular smooth muscle; western blottings

Aging is the major risk factor for the development of vascular proliferative diseases such as hypertension and atherosclerosis that lead to coronary vascular disease and stroke. Increased cytokine levels, due to increased inflammatory response of the vessel wall, have been implicated in the development of atherosclerosis in aged patients. The matrix metalloproteinase-9 (MMP-9) ,induced in response to cytokines plays an important role in VSM cell migration from media to intima. Our preliminary observations indicate that VSM cell proliferation is significantly increased in aged rats compared to the young rats. We have observed that IL-1beta-stimulated increase in MMP-9 secretion is mediated through activation of ERK +. We have also observed that nitric oxide (NO) inhibits ERIC activation that leads to the inhibition of MMP- 9 secretion. Despite the significant progress made in the understanding of the IL-1beta-mediated intracellular regulatory mechanisms that increase MMP-9 secretion, the mechanism of action of the inhibitory agents, namely NO, that decreases MMP-9 secretion remain obscure. An understanding of these inhibitory mechanisms can aid in the development of therapeutic strategies to inhibit vascular proliferative diseases associated with old age. The overall hypothesis of this proposal is that decrease in NO-mediated inhibition of MMP-9 secretion is a critical determinant of the increased VSM cell migration and proliferation observed in aged patients. Two specific aims will be pursued. 1) To determine whether ERK/MMP-9 signaling in response to IL-1beta stimulation is increased in VSM cells of aged rats compared to the young rats. 2) To determine whether eNOS gene transfer in VSM cells isolated from aged rats will alleviate the differences between old and young animals for IL-1beta-stimulated ERK activation, MMP-9 secretion and VSM cell migration and proliferation. The investigation will provide new information concerning the mechanisms of NO regulation of MMP-9 secretion and is likely to explain how the endothelial dysfunction in old age can lead to vascular proliferative diseases.

衰老是血管增生性疾病发展的主要危险因素，如高血压和动脉粥样硬化，导致冠状动脉疾病和中风。由于血管壁的炎症反应增加而导致的细胞因子水平增加与老年患者动脉粥样硬化的发展有关。基质金属蛋白酶-9（MMP-9）在细胞因子诱导的VSM细胞从中膜向内膜迁移中起重要作用。我们的初步观察表明，VSM细胞增殖显着增加，在老年大鼠相比，年轻的大鼠。我们已经观察到，IL-1 β刺激的MMP-9分泌增加是通过ERK +激活介导的。我们还观察到，一氧化氮（NO）抑制ERIC激活，导致MMP- 9分泌的抑制。尽管在了解IL-1 β介导的增加MMP-9分泌的细胞内调节机制方面取得了重大进展，但抑制剂即NO减少MMP-9分泌的作用机制仍然不清楚。对这些抑制机制的理解可以帮助开发治疗策略以抑制与老年相关的血管增殖性疾病。该建议的总体假设是，NO介导的MMP-9分泌抑制的减少是老年患者中观察到的VSM细胞迁移和增殖增加的关键决定因素。将追求两个具体目标。1)确定老年大鼠VSM细胞对IL-1 β刺激的ERK/MMP-9信号转导是否比年轻大鼠增加。2)目的：探讨eNOS基因转染老年大鼠VSM细胞后，是否能改善老年和青年大鼠在IL-1 β刺激的ERK激活、MMP-9分泌及VSM细胞迁移和增殖方面的差异。本研究将为NO调节MMP-9分泌的机制提供新的信息，并可能解释老年内皮功能障碍如何导致血管增殖性疾病。