Superoxide and Vascular Function in Heart Failure

描述（由申请人提供）：心力衰竭（HF）是一个非常重要的临床问题。内皮功能损害与心衰有关，并可能通过增加心室后负荷促进心衰的进展。由于氧化应激是内皮功能的重要决定因素，本研究旨在：1)确定细胞外超氧化物歧化酶（extracellular superoxide dismutase, ecSOD）作为一种重要的抗氧化剂在HF患者内皮功能保护中的作用；2)确定细胞内铜锌超氧化物歧化酶（CuZnSOD）在HF患者内皮功能保护中的作用。在Aim 1中，我们将对缺乏ecSOD小鼠的主动脉环进行离体研究，以确定内源性ecSOD对HF内皮功能保护的贡献。过表达人ecSOD的小鼠也将进行离体研究，以确定ecSOD的增加是否能保护HF的内皮功能。在Aim 2中，我们将在体外研究CuZnSOD缺乏小鼠的主动脉环，以及CuZnSOD过表达转基因小鼠的主动脉环，以确定细胞内超氧化物清除在HF中的作用。总的来说，这些研究将为氧化应激和血管功能在心衰中的作用提供重要的见解。

DESCRIPTION (provided by applicant): Heart failure (HF) is an enormously important clinical problem. Impairment of endothelial function is associated with HF, and may contribute to the progression of HF by increasing ventricular afterload. As oxidative stress is a important determinant of endothelial function, these studies aim to: 1) determine the role of extracellular superoxide dismutase (ecSOD), an important antioxidant, in protection of endothelial function in HF, and 2) determine the role of the intracellular copper-zinc SOD (CuZnSOD) in the protection of endothelial function in HF. For Aim 1, aortic rings from mice deficient in ecSOD will be studied ex vivo to determine the contribution of endogenous ecSOD to preservation of endothelial function in HF. Mice overexpressing human ecSOD will also be studied ex vivo to determine if increases in ecSOD can protect endothelial function in HF. In Aim 2, aortic rings from mice deficient in CuZnSOD, as well as rings from transgenic mice overexpressing CuZnSOD will be studied ex vivo to determine the role of intracellular superoxide scavenging in HF. Collectively, these studies will lend important insights into the role of oxidative stress and vascular function in HF.