The Role of Shear Stress in Heart Failure

描述（由申请人提供）：毫无疑问，随着人口老龄化，西方世界充血性心力衰竭（CHF）的发病率正在增加。NHLBI估计，超过200万美国人患有心力衰竭，每年诊断出约50万新病例。本提案的总体目标是了解血管氧化应激在CHF中的作用。中心假设是，减少壁剪切应力（WSS）在微循环和反向流在较大的血管将增加O2-生产主要介导的NADPH氧化酶系统，从而降低血管的生物利用度NO。这上调NADPH氧化酶被认为是通过内皮细胞骨架的负载和变形的变化介导。为了验证这个假设和其他假设，我们设定了以下五个具体目标：1）记录和说明物理负载（血流、压力和WSS）作用于清醒的自由放养动物的血管内皮，在CHF的进展过程中精确和分析; 2）确定目标1中确定的低和负WSS作为急性血流减少和血流逆转期间离体血管中O2-产生的初始刺激的作用; 3）在目的1和2中确定的HF进展期间，由于微循环中的流量减少和大循环中的流量逆转增加，建立NO和O2-之间的平衡的长期重塑; 4）在目的3中阐明NADPH氧化物以及NO的其它调节酶（eNOS）和O2-歧化酶（SOD）在限制NO生物利用度中的作用;和5）量化由于目的2-4中的氧化失衡引起的血管内皮和平滑肌细胞功能障碍。记录的在体血压、流量和WSS数据将在CHF进展期间用经验模型分解方法表征。血流动力学测量将与NO代谢产物的产生以及eNOS和SOD的表达相关。该项目的贡献是在数学上表征血流和血压的非平稳，非线性和随机特征，作用于血管内皮细胞的剪切应力，并显示低和负WSS的升级如何对内皮功能，超氧化物生成，SOD和eNOS表达产生不利影响。

DESCRIPTION (provided by applicant): There is no doubt that the incidence of congestive heart failure (CHF) in the Western world is increasing as the population ages. The NHLBI has estimated that more than 2 million Americans have heart failure, with about half a million new cases diagnosed each year. The general objective of this proposal is to understand the role of vascular oxidative stress in CHF. The central hypothesis is that the reduced wall shear stress (WSS) in the microcirculation and reverse flow in the larger vessels will increase O2- production largely mediated by the NADPH oxidase system and hence reduce the vascular bioavailability of NO. This upregulation of NADPH oxidase is thought to be mediated through changes in endothelial cytoskeletal loading and deformation. To test this and other hypotheses, we set the following five Specific Aims: 1) To document and state the physical loading (blood flow, pressure and WSS) acting on the blood vessel endothelium in awake, free ranging animals precisely and analytically during the progression of CHF; 2) To identify the role of low and negative WSS determined in Aim 1 as the initial stimuli for O2- production in ex vivo vessels during acute flow reduction and flow reversal; 3) To establish the remodeling of the balance between NO and O2- chronically during the progression of HF due to reduced flow in the microcirculation and increased flow reversal in the macrocirculation identified in Aims 1 and 2; 4) To elucidate the role of NADPH oxide as well as other regulatory enzymes for NO (eNOS) and O2- dismutase (SOD) in limiting NO bioavailability in Aim 3; and 5) To quantify the endothelial and smooth muscle cell dysfunction of blood vessels due to the oxidative imbalance in Aims 2-4. The recorded in vivo blood pressure, flow and WSS data will be characterized with the empirical model decomposition method during the progression of CHF. The hemodynamic measurements will be correlated with the production of NO metabolites and expression of eNOS and SOD. The contribution of this project is to mathematically characterize the non-stationary, nonlinear, and stochastic features of the blood flow and blood pressure, the shear stress acting on vascular endothelial cells, and to show how escalation of low and negative WSS can have a detrimental effect on endothelial function, superoxide production, SOD and eNOS expression.