Endothelial Oxidative Stress and Inflammation:Mechanisms and Human Studies

描述（由申请人提供）：慢性心力衰竭（CHF）是一种以内皮功能障碍和神经激素激活为特征的全身炎症性疾病。慢性心力衰竭（CHF）患者消耗了很大比例的医疗资源，因为他们经常因急性失代偿性心力衰竭（ADHF）住院，这是基于静脉充血的临床证据。越来越多的证据表明：(1)静脉充血是ADHF发病率和死亡率的主要预测因素；（ii）静脉充血在症状恶化前几周就开始出现，导致需要紧急住院治疗。尽管这些临床证据表明静脉充血在ADHF的病理生理中起作用，但静脉充血对血管内皮（人体最大的内分泌/旁分泌器官）和神经激素激活的生物力学驱动作用仍未被探索。我们使用一种新颖、安全的静脉内皮采样方法以及蛋白质和基因表达分析的初步数据表明：(1)ADHF住院患者的临床充血与内皮细胞氧化/炎症程序的激活有关；并且，在机制上，（ii）正常受试者的实验性充血足以促进内皮和神经激素的激活。本研究的中心假设是，在CHF患者中，静脉充血作为一种独立的氧化/炎症刺激，调节与内皮和神经激素激活相关的关键遗传调控事件，从而影响ADHF的发展和消退。我们建议使用双管设计来研究这一假设，这将使我们能够研究“体积敏感”基因和蛋白质，内皮细胞中的整体基因表达，以及血浆中神经激素活性对以下两种情况的反应：(i) n=24代偿性、无ADHF近期病史的大容量CHF患者以及n=24代偿性、近期ADHF病史的患者的急性实验性充血（Aim 1）；相反，（ii）急性治疗性去充血，由“高”量vs。“标准”容积超滤，在n=48例临床有静脉充血证据的ADHF住院患者中进行（Aim 2）。2007年，美国国立卫生研究院将炎症确定为“需要广泛合作研究的公共卫生关键领域”。如果成功，我们的研究(i)将模拟生物力学驱动的途径，这些途径启动并维持静脉炎症，从而促进CHF从代偿到急性失代偿的临床转变；在等式的另一边，（ii）将揭示有助于预防和/或解决ADHF的抗氧化/抗炎级联反应。总的来说，我们的数据可能为未来的研究提供了强有力的理论依据，这些研究将使用基于分子的方法，在独特的个体中预防和治疗ADHF。

DESCRIPTION (provided by applicant): Chronic heart failure (CHF) is a systemic inflammatory disease characterized by endothelial dysfunction and neurohormonal activation. Patients with chronic heart failure (CHF) consume a large percentage of health care resources as they are frequently hospitalized for acute decompensated heart failure (ADHF) based on clinical evidence of venous congestion. Accumulating evidence suggests that (i) venous congestion is a major predictor of morbidity and mortality in ADHF; and (ii) venous congestion begins to occur weeks before symptoms worsen resulting in a need for urgent in-hospital therapy. Despite this clinical evidence suggesting a role for venous congestion in the pathophysiology of ADHF, the biomechanically-driven effects of venous congestion on the vascular endothelium (the largest endocrine/paracrine organ of the body) and on neurohormonal activation remain unexplored. Our preliminary data using a novel, safe method of venous endothelial sampling coupled with analysis of protein and gene expression, indicate that: (i) clinical congestion, in patients hospitalized for ADHF, is associated with endothelial activation of the oxidative/inflammatory programs; and, mechanistically, (ii) that experimental congestion, in normal subjects, is sufficient to promote endothelial and neurohormonal activation. The central hypothesis of the proposed research is that venous congestion, in patients with CHF, acts as an independent oxidative/inflammatory stimulus which modulates key genetic regulatory events related to endothelial and neurohormonal activation, and, thereby, to the development and the resolution of ADHF. We propose to investigate this hypothesis using a two-pronged design which will allow us to study "volume- sensitive" genes and proteins, and global gene expression in endothelial cells, as well as neurohormonal activity in plasma in response to both (i) acute experimental congestion among n=24 compensated, euvolemic CHF patients with no recent history of ADHF, as well as among n=24 compensated patients with recent history of ADHF (Aim 1); and, conversely (ii) acute therapeutic decongestion, by "high" volume vs. "standard" volume ulltrafiltration, among n=48 patients hospitalized for ADHF with clinical evidence of venous congestion (Aim 2). In 2007, the NIH identified inflammation as "a key area of public health in need of broad-based collaborative research". If successful, our studies (i) will model the biomechanically-driven pathways that initiate and sustain inflammation in veins and thereby contribute to the clinical transition from compensation to acute decompensation in CHF; and, on the other side of the equation, (ii) will uncover those anti-oxidant/anti- inflammatory cascades that contribute to the prevention and/or resolution of ADHF. Overall, our data may provide a strong rationale for future studies that will use a molecular-based approach, in the unique individual, for the prevention and treatment of ADHF.