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）： 类风湿性关节炎 (RA) 等慢性炎症性疾病与心血管疾病 (CVD) 的过早发生有关，患有 RA 的美国退伍军人的死亡率是普通人群中同龄男性的两倍以上，这是一种风险。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，需要其他针对慢性炎症的血管效应器的方法。我们研究计划的长期目标是了解 Nox1 NADPH 氧化酶促进血管疾病发病机制的机制，并确定减少 CVD 的新治疗靶点。我们的研究结果还建立了表皮生长因子受体 (EGFR) 激活与血管平滑肌细胞 (SMC) 生长和迁移中的 Nox1 之间的联系。整合这些发现并探索慢性炎症增加 CVD 的机制，我们探索了慢性炎症会增加循环 EGF 样配体，从而诱导血管 Nox1 表达并引发 SMC 细胞因子激活，从而促进血管疾病。 ：目标 1：确定 EGF 样配体通过 Nox1 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) Nox1 剪接的作用。异构体；(2) ROS 诱导的 ROS 机制，以及 (3) EGF 样配体对 SMC 的启动作用？ 目标 2：确定中断 SMC 中的 EGFR-Nox1 激活是否会阻止慢性炎症中血管疾病的加速发展。在患有炎性关节炎模型的转基因小鼠中诱导新内膜增生，并检查 (1) 平滑肌细胞特异性 EGFR 缺陷 (2) 缺陷的影响； Nox1 的磷酸化；(3) Nox1 磷酸化对新内膜形成的抑制 目标 3：确定血浆 EGF 样配体是否能识别出患有血管疾病的高风险的 RA 患者。由生物样本和纵向临床数据组成的注册表进行调查 RA 患者血浆 EGF 样配体与心血管发病率和死亡率的关联性研究的成功完成将为了解 RA 等慢性炎症增加 CVD 发病率和死亡率的机制提供新的见解。我们提出的研究是，我们的研究结果将为开发治疗患有慢性炎症和血管疾病的退伍军人的特定靶向疗法提供新策略。