Yan Simin, Resta Thomas C, Jernigan Nikki L
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Antioxidants (Basel). 2020 Oct 15;9(10):999. doi: 10.3390/antiox9100999.
Elevated resistance of pulmonary circulation after chronic hypoxia exposure leads to pulmonary hypertension. Contributing to this pathological process is enhanced pulmonary vasoconstriction through both calcium-dependent and calcium sensitization mechanisms. Reactive oxygen species (ROS), as a result of increased enzymatic production and/or decreased scavenging, participate in augmentation of pulmonary arterial constriction by potentiating calcium influx as well as activation of myofilament sensitization, therefore mediating the development of pulmonary hypertension. Here, we review the effects of chronic hypoxia on sources of ROS within the pulmonary vasculature including NADPH oxidases, mitochondria, uncoupled endothelial nitric oxide synthase, xanthine oxidase, monoamine oxidases and dysfunctional superoxide dismutases. We also summarize the ROS-induced functional alterations of various Ca and K channels involved in regulating Ca influx, and of Rho kinase that is responsible for myofilament Ca sensitivity. A variety of antioxidants have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, supporting the role of ROS in the development of pulmonary hypertension. A better understanding of the mechanisms by which ROS enhance vasoconstriction will be useful in evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension.
长期缺氧暴露后肺循环阻力升高会导致肺动脉高压。通过钙依赖性和钙敏化机制增强肺血管收缩，促成了这一病理过程。由于酶促生成增加和/或清除减少，活性氧（ROS）通过增强钙内流以及激活肌丝敏化参与肺动脉收缩增强，从而介导肺动脉高压的发展。在此，我们综述了慢性缺氧对肺血管系统内ROS来源的影响，这些来源包括NADPH氧化酶、线粒体、解偶联的内皮型一氧化氮合酶、黄嘌呤氧化酶、单胺氧化酶和功能失调的超氧化物歧化酶。我们还总结了ROS诱导的各种参与调节钙内流的钙通道和钾通道以及负责肌丝钙敏感性的Rho激酶的功能改变。已证明多种抗氧化剂在肺动脉高压动物模型中具有有益的治疗作用，支持了ROS在肺动脉高压发展中的作用。更好地理解ROS增强血管收缩的机制将有助于评估抗氧化剂治疗肺动脉高压的疗效。
