Abstract
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 Ca2+ and K+ channels involved in regulating Ca2+ influx, and of Rho kinase that is responsible for myofilament Ca2+ 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.
Highlights
The pulmonary circulation is normally a low resistance and low-pressure system with a mean pulmonary arterial pressure less than 20 mmHg [1]
Pulmonary hypertension (PH) is diagnosed by resting mean pulmonary arterial pressure (mPAP) greater than 20 mmHg accompanied by pulmonary vascular resistance ≥ 3 Wood Units in pre-capillary PH, and classified as either idiopathic
Since the reduction of electrons in their outer nitric oxide synthase (eNOS) activity by nitric oxide (NO) is not related to cell viability, eNOS expression, subcellular localization, or phosphorylation of eNOS [128], the mechanism by which reactive oxygen species (ROS) mediate NO-induced eNOS inhibition remains unclear in this cell model
Summary
The pulmonary circulation is normally a low resistance and low-pressure system with a mean pulmonary arterial pressure (mPAP) less than 20 mmHg [1]. Increased reactive oxygen species (ROS) have been widely reported to mediate reported to mediate augmented pulmonary arterial constriction [3,12,18,19,20,22,24,25,26,27,28] (Figure 1), and augmented pulmonary arterial constriction [3,12,18,19,20,22,24,25,26,27,28] (Figure 1), and antioxidation strategies antioxidation strategies provide therapeutic efficacy in animal models of PH [3,29,30,31,32,33,34,35,36,37]. There are three known SOD isoforms found in located extracellularly [38].
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