Premature Atherosclerosis in Rheumatic Diseases

风湿性疾病中的过早动脉粥样硬化

• 批准号: 6734069
• 负责人: Mary K Crow
• 金额: $ 35.96万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6734069
• 关键词: CD1 molecule; atherosclerosis; biomarker; blood chemistry; clinical research; early diagnosis; gene expression; human subject; immunofluorescence technique; medical complication; monocyte; pathologic process; platelets; polymerase chain reaction; rheumatoid arthritis; systemic lupus erythematosus; western blottings

DESCRIPTION (provided by applicant): While the renal and central nervous system manifestations of systemic lupus erythematosus (SLE) often present as compelling indications for aggressive cytotoxic therapy, recent data demonstrate that a significant proportion of those patients have asymptomatic cardiovascular disease (CVD) that goes unrecognized and can eventually result in important morbidity and mortality. Our center has performed a major case-control study to document the prevalence of premature atherosclerosis among patients with SLE and is extending that study to patients with rheumatoid arthritis (RA). Although SLE patients and controls were comparable in CVD risk factors, atherosclerosis (carotid plaque) was more prevalent in SLE patients (37 vs. 15%, p<0.001). To elucidate the underlying mechanisms that account for premature atherosclerosis in these patients, a panel of proinflammatory mediators in peripheral blood was assessed. The data were unrevealing of relevant mechanisms, as SLE patients either with or without carotid plaque expressed elevated levels of cytokines, soluble adhesion molecules, and soluble CD154. However, important clues regarding potential disease mechanisms were revealed based on analysis of microarray data from a subset of the SLE study subjects. The data have stimulated the hypothesis that activation of the platelet-monocyte-endothelial cell axis contributes to premature atherosclerosis in SLE. Preliminary data suggest that specific gene products that may be important mediators of vascular damage are increased in expression in SLE patients with carotid plaque. The proposed research will investigate the expression of these vascular mediators in our cohort of SLE and RA patients characterized for carotid disease and will study the functional relationship among the cells that express these factors. The specific aims are: 1) to investigate the expression of CD154 in rheumatic disease patients with premature atherosclerosis; 2) to investigate the expression of potential biomarkers of vascular disease in rheumatic disease patients with premature atherosclerosis; and 3) to determine the role of platelets and monocytes in generating pro-atherogenic mediators. Early identification of biomarkers in those patients who will go on to develop premature atherosclerotic disease and institution of biomarkers in those patients who will go on to develop premature atherosclerotic disease and institution of appropriate therapy should have a major impact on patient health and survival.

描述（由申请人提供）： 虽然系统性红斑狼疮 (SLE) 的肾脏和中枢神经系统表现通常是积极细胞毒治疗的令人信服的指征，但最近的数据表明，这些患者中有很大一部分患有无症状心血管疾病 (CVD)，而这些疾病未被识别出来，最终可能导致严重的发病率和死亡率。我们中心进行了一项重要的病例对照研究，以记录 SLE 患者中过早动脉粥样硬化的患病率，并将该研究扩展到类风湿性关节炎 (RA) 患者。尽管 SLE 患者和对照组在 CVD 危险因素方面具有可比性，但动脉粥样硬化（颈动脉斑块）在 SLE 患者中更为普遍（37% vs. 15%，p<0.001）。为了阐明这些患者过早动脉粥样硬化的潜在机制，对外周血中的一组促炎介质进行了评估。这些数据并未揭示相关机制，因为有或没有颈动脉斑块的 SLE 患者表达的细胞因子、可溶性粘附分子和可溶性 CD154 水平升高。然而，基于对 SLE 研究对象子集的微阵列数据的分析，揭示了有关潜在疾病机制的重要线索。这些数据激发了这样的假设：血小板-单核细胞-内皮细胞轴的激活导致系统性红斑狼疮患者过早发生动脉粥样硬化。初步数据表明，可能是血管损伤重要介质的特定基因产物在患有颈动脉斑块的系统性红斑狼疮患者中表达增加。拟议的研究将调查我们以颈动脉疾病为特征的 SLE 和 RA 患者队列中这些血管介质的表达，并将研究表达这些因子的细胞之间的功能关系。具体目的是：1）研究CD154在风湿病合并早发动脉粥样硬化患者中的表达情况； 2) 探讨早发动脉粥样硬化的风湿病患者血管疾病潜在生物标志物的表达情况； 3) 确定血小板和单核细胞在产生促动脉粥样硬化介质中的作用。早期识别那些将继续发展为过早动脉粥样硬化疾病的患者的生物标志物以及为那些将继续发展为过早动脉粥样硬化疾病的患者建立生物标志物并建立适当的治疗应该对患者的健康和生存产生重大影响。