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World J Cardiol. Oct 26, 2010; 2(10): 316-324
Published online Oct 26, 2010. doi: 10.4330/wjc.v2.i10.316
Contribution of oxidative stress to pulmonary arterial hypertension
Vincent G DeMarco, Adam T Whaley-Connell, James R Sowers, Javad Habibi, Kevin C Dellsperger
Vincent G DeMarco, Adam T Whaley-Connell, James R Sowers, Javad Habibi, Kevin C Dellsperger, Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, United States
Vincent G DeMarco, Adam T Whaley-Connell, James R Sowers, Javad Habibi, Diabetes and Cardiovascular Laboratory, University of Missouri School of Medicine, Columbia, MO 65212, United States
Vincent G DeMarco, James R Sowers, Kevin C Dellsperger, Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, United States
Adam T Whaley-Connell, James R Sowers, Harry S Truman Veterans Affair Medical Center, Columbia, MO 65201, United States
Author contributions: DeMarco VG reviewed the literature and crafted the article; Dellsperger KC assisted with crafting and revising the article; Whaley-Connell AT, Habibi J and Sowers JR each assisted with providing important intellectual content and editorial assistance with successive drafts of the manuscript.
Correspondence to: Dr. Vincent G DeMarco, Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, United States. demarcov@missouri.edu
Telephone: +1-573-8847319 Fax: +1-573-8847310
Received: August 3, 2010
Revised: August 18, 2010
Accepted: August 25, 2010
Published online: October 26, 2010
Abstract

Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.

Keywords: Pulmonary arterial hypertension; Rosuvastatin; Oxidative stress; Nicotinamide adenine dinucleotide phosphate oxidase; Statins