The Role of Shear Stress in Heart Failure

描述(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，每年约有50万新诊断病例。这项建议的总体目标是了解血管氧化应激在CHF中的作用。中心假说是，微循环中壁面切应力(WSS)的降低和较大血管中的反向流动将增加主要由NADPH氧化酶系统介导的O2-的产生，从而降低血管中NO的生物利用度。这种NADPH氧化酶的上调被认为是通过内皮细胞骨架负荷和变形的变化来调节的。为了验证这一假设和其他假设，我们设定了以下五个具体目标：1)记录和陈述在CHF进展过程中清醒、自由活动的动物对血管内皮细胞的物理负荷(血流、压力和WSS)；2)确定目标1中确定的低和负的WSS在急性流量减少和血流逆转期间作为体外血管产生O2-的初始刺激的作用；3)在由于目标1和2中确定的微循环流量减少和大循环流量逆转增加而导致的HF进展过程中，建立NO和O2之间平衡的重建；4)阐明NADPH氧化物以及其他NO调节酶(ENOS)和超氧化物歧化酶(SOD)在限制AIMS 3中NO生物利用度中的作用；以及5)量化AIMS 2-4中氧化失衡导致的血管内皮细胞和平滑肌细胞功能障碍。在CHF进展过程中，记录的活体血压、血流量和WSS数据将用经验模型分解方法进行表征。血流动力学测量将与NO代谢产物的产生以及eNOS和SOD的表达相关联。这个项目的贡献在于从数学上刻画血流和血压的非平稳、非线性和随机性特征，以及作用于血管内皮细胞的剪切力，并展示低和负WSS的升级如何对内皮功能、超氧化物歧化产物、超氧化物歧化酶和eNOS的表达产生不利影响。

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.