MECHANISMS OF VASCULAR DISEASE IN DIABETES

描述（由申请人提供）：糖尿病患者存在一系列合并症的高风险，包括心血管疾病（CVD）。在2型糖尿病患者中观察到的心血管事件风险增加与这些患者中倾向于共存的心血管和代谢紊乱的一系列风险因素相关。尽管成功实施了循证策略，但许多人在首次事件发生前未被确定为高风险，其他人尽管进行了最佳管理，仍继续经历心血管事件。虽然这种风险的大部分可归因于常规风险因素的存在，如高血糖症、高脂血症、高血压，但这种风险的大量负担仍然无法解释。炎症介质和生长因子在动脉粥样硬化的发生发展中起着重要的作用。因此，本提案的总体目标侧重于进行纵向评估，以确定新型生物标志物结缔组织生长因子（CTGF）在2型糖尿病受试者大血管和微血管疾病发生/进展中的作用和贡献，并确定存在微血管疾病时CTGF增加是否可预测大血管疾病的发生。我们的初步研究结果，基于2型糖尿病患者队列的横断面数据，表明心血管事件的发生与CTGF水平升高独立相关。我们的研究结果表明，有心肌梗死（MI）或冠状动脉疾病（CAD）病史的糖尿病患者血浆CTGF水平明显高于既往无心血管事件的患者。我们还发现，在这些2型糖尿病受试者中，血浆CTGF循环水平与视网膜病变ETDRS评分以及白蛋白排泄率（AER）之间存在强相关性。此外，我们的研究结果表明，CTGF表达诱导ApoE-/-敲除小鼠动脉粥样硬化与对照小鼠相比，主动脉。因此，基于我们生成的初步数据，我们假设较高水平的循环CTGF反映了高血压、内皮功能障碍和炎症引起的持续血管损伤，并且CTGF水平升高将预测未来心血管事件和进行性视网膜病变和肾病的风险更大。为了验证我们的假设，我们提出了以下具体目标：1）确定血浆CTGF水平是否预测2型糖尿病患者未来的心血管事件和进行性视网膜病变和肾病。2)确定CTGF在糖尿病血管疾病的发生和发展中的作用和贡献。拟议的研究应将CTGF确定为糖尿病血管疾病的病理学重要风险因素，这将成为定义介入治疗新靶点的基础。

DESCRIPTION (provided by applicant): Diabetic patients are at high risk of a range of comorbid complications, including cardiovascular disease (CVD). The increased risk of cardiovascular events seen in patients with type 2 diabetes is associated with a cluster of risk factors for cardiovascular and metabolic disorders that tend to coexists in these patients. Despite successful implementation of evidence based strategies, many individuals are not identified as high risk before their first event and others continue to experience cardiovascular events despite optimal management. While much of this risk is attributable to the presence of conventional risk factors, such as hyperglycemia, hyperlipidemia, hypertension, a substantial burden of this risk remains unexplained. Inflammatory mediators and growth factors are increasingly recognized as playing important roles in the development of atherosclerosis. Therefore the overall objective of this proposal focuses on performing longitudinal assessment to define the role and contribution of a novel biomarker, connective tissue growth factor (CTGF), in the initiation/ progression of macrovascular and microvascular disease in subjects with type 2 diabetes and to determine whether increases in CTGF in the presence of microvascular disease will predict development of macrovascular disease. Our preliminary findings, based on cross-sectional data generated from a cohort of type 2 diabetic patients, suggest that the occurrence of cardiovascular events is independently linked to elevations in CTGF level. Our results demonstrate that diabetic patients with a prior history of myocardial infarction (MI) or coronary artery disease (CAD) have significantly higher levels of plasma CTGF than patients who have not had a prior cardiovascular event. We also uncovered a strong association between circulating levels of plasma CTGF and retinopathy ETDRS scores as well as albumin excretion rate (AER) in these type 2 diabetic subjects. In addition, our findings demonstrate that CTGF expression is induced in aorta of ApoE-/- knockout mice with atherosclerosis compared to control mice. Therefore, based on the preliminary data we generated, we hypothesize that higher levels of circulating CTGF reflect ongoing vascular damage from hypertension, endothelial dysfunction and inflammation, and that elevated CTGF levels will predict greater risk for future cardiovascular events and progressive retinopathy and nephropathy. To test our hypothesis we propose the following specific aims: 1) Determine whether plasma CTGF levels predict future cardiovascular events and progressive retinopathy and nephropathy in individuals with type 2 diabetes. 2) Determine the role and contribution of CTGF to the initiation and progression of diabetic vascular disease. The proposed studies should establish CTGF as a pathologically-important risk factor for diabetic vascular disease that will form the basis for defining new targets for interventional therapy.