Regulation of the Nox1 NADPH Oxidase in Vascular Smooth Muscle Cells

血管平滑肌细胞中 Nox1 NADPH 氧化酶的调节

• 批准号: 9138279
• 负责人: FRANCIS J MILLER
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138279
• 关键词: Address; Adrenal Cortex Hormones; Age; Animal Model; Antirheumatic Agents; Aorta; Atherosclerosis; Attenuated; Award; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cessation of life; Chronic; Clinical; Clinical Data; Collagen-Induced Arthritis; Complex; Cytokine Activation; Data; Development; Disease; Disease model; Dose; EGF gene; Epidermal Growth Factor Receptor; Funding; General Population; Genetic Transcription; Goals; Human; Hyperplasia; Inflammation; Inflammatory; Inflammatory Arthritis; Injury; Interruption; Ligands; Link; Lipids; Mediating; Modeling; Morbidity - disease rate; Mus; Muscle Cells; Myocardial Ischemic Preconditioning; NADPH Oxidase; Outcome; Pathogenesis; Patients; Phosphorylation; Plasma; Population; Post-Translational Protein Processing; Primates; Production; Protein Isoforms; RNA Splicing; Receptor Activation; Regulation; Reporting; Research; Rheumatoid Arthritis; Risk; Role; Serum; Smooth Muscle Myocytes; Specimen; Superoxides; Syndrome; Testing; Threonine; Vascular Diseases; Vascular Smooth Muscle; Veterans; Work; arthritis registry; base; cardiovascular disorder risk; cardiovascular risk factor; cell growth; cell motility; cigarette smoking; cohort; cytokine; disorder risk; high risk; inflammatory marker; insight; men; migration; molecular targeted therapies; mortality; new therapeutic target; non-compliance; novel; post-traumatic stress; premature; prevent; programs; public health relevance; systematic review; targeted treatment

 DESCRIPTION (provided by applicant): Chronic inflammatory diseases, such as, rheumatoid arthritis (RA), are associated with premature development of cardiovascular disease (CVD). Mortality rates among US Veterans with RA are more than twice that of age-matched men in the general population, a risk that appears to be higher than that observed in other RA cohorts. Despite strong evidence that chronic inflammation accelerates CVD, currently available treatments are not sufficient to prevent the accelerated CVD. Therefore, other approaches that target the vascular effectors of chronic inflammation are needed. The long-term goal of our research program is to understand the mechanisms by which the Nox1 NADPH oxidase contributes to the pathogenesis of vascular disease and identify novel therapeutic targets to reduce CVD. In work that was funded by a VA Merit Award, we have identified mechanisms of cytokine-mediated Nox1 activation. Our findings have also established a link between epidermal growth factor receptor (EGFR) activation and Nox1 in vascular smooth muscle cell (SMC) growth and migration. In this renewal application, our objective is to integrate these findings and explore the mechanism by which chronic inflammation increases CVD. We hypothesize that chronic inflammation increases circulating EGF-like ligands, which induces vascular Nox1 expression and primes SMCs to cytokine activation, thereby promoting vascular disease. We will address the following specific aims: Aim 1: Determine the mechanism by which EGF-like ligands accelerate vascular injury via Nox1 activation. Proposed studies will be performed in cultured human vascular SMCs and assess (1) the role of Nox1 splice isoforms; (2) ROS-induced ROS mechanisms, and (3) priming effects of EGF-like ligands on SMCs? Aim 2: Determine whether interrupting EGFR-Nox1 activation in SMCs prevents accelerated development of vascular disease in chronic inflammation. Proposed studies will induce neointimal hyperplasia in genetically modified mice subjected to a model of inflammatory arthritis and examine the effects of (1) smooth muscle cell-specific deficiency of EGFR; (2) deficiency of Nox1; and (3) the inhibition of Nox1 phosphorylation, on neointimal formation. Aim 3: Determine if plasma EGF-like ligands identify RA patients at high risk for developing vascular disease. Proposed studies will utilize the Veterans Affairs Rheumatoid Arthritis (VARA) registry consisting of bio-specimens and longitudinal clinical data to investigate the association of plasma EGF-like ligands in RA patients with cardiovascular morbidity and mortality. Successful completion of these studies will provide new insights into the mechanisms by which chronic inflammation, such as RA, increases morbidity and mortality of CVD. A positive clinical impact of our proposed studies is that our findings will provide new strategies fr the development of specific targeted therapeutics for the treatment of Veterans with chronic inflammation and vascular disease.

 描述（由申请人提供）： 慢性炎症性疾病，如类风湿性关节炎（RA），与心血管疾病（CVD）的过早发展有关。美国退伍军人类风湿关节炎患者的死亡率是一般人群中年龄匹配男性的两倍多，这种风险似乎高于其他类风湿关节炎队列中观察到的风险。尽管有强有力的证据表明慢性炎症会加速CVD，但目前可用的治疗方法不足以预防加速的CVD。因此，需要靶向慢性炎症的血管效应物的其他方法。我们研究计划的长期目标是了解Nox 1 NADPH氧化酶促进血管疾病发病机制的机制，并确定新的治疗靶点以减少CVD。在由VA Merit Award资助的工作中，我们已经确定了尼古丁介导的Nox 1激活机制。我们的研究结果还建立了表皮生长因子受体（EGFR）激活和血管平滑肌细胞（SMC）生长和迁移中的Nox 1之间的联系。在这次更新申请中，我们的目标是整合这些发现，并探索慢性炎症增加CVD的机制。我们假设慢性炎症增加了循环中EGF样配体，从而诱导血管Nox 1表达并引发SMC细胞因子活化，从而促进血管疾病。我们将解决以下具体目标：目的1：确定EGF样配体通过Nox 1激活加速血管损伤的机制。拟议的研究将在培养的人血管SMC中进行，并评估（1）Nox 1剪接异构体的作用;（2）ROS诱导的ROS机制，以及（3）EGF样配体对SMC的引发作用？目的2：确定是否中断EGFR-Nox 1在SMC中的激活防止慢性炎症中血管疾病的加速发展。拟定的研究将在接受炎性关节炎模型的转基因小鼠中诱导新生内膜增生，并检查（1）EGFR的平滑肌细胞特异性缺陷;（2）Nox 1缺陷;和（3）Nox 1磷酸化抑制对新生内膜形成的影响。目的3：确定血浆EGF样配体是否能识别RA患者发生血管疾病的高风险。拟议的研究将利用退伍军人事务部风湿性关节炎（VARA）登记处，包括生物标本和纵向临床数据，以调查 类风湿性关节炎患者血浆表皮生长因子样配体与心血管疾病发病率和死亡率的关系这些研究的成功完成将为慢性炎症（如RA）增加CVD发病率和死亡率的机制提供新的见解。我们提出的研究的一个积极的临床影响是，我们的研究结果将提供新的策略，用于开发治疗慢性炎症和血管疾病的退伍军人的特异性靶向疗法。