2013 hypertension-7

 

Hyperoxia Synergizes with Mutant BMPR2 to Cause Metabolic Stress, Oxidant Injury, and Pulmonary Hypertension.

Am J Respir Cell Mol Biol. 2013 Jun 6.

Fessel JP, Flynn CR, Robinson LJ, Penner NL, Gladson S, Kang C, Wasserman DH, Hemnes AR, West JD.

Vanderbilt University Medical Center, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Nashville, Tennessee, United States ; joshua.p.fessel@vanderbilt.edu.

Abstract

Pulmonary arterial hypertension (PAH) has been associated with a number of different but interrelated pathogenic mechanisms. Metabolic and oxidative stresses have been shown to play important pathogenic roles in a variety of model systems. However, many of these relationships remain at the level of association. We sought to establish a direct role for metabolic stress and oxidant injury in the pathogenesis of PAH. Mice that universally express a disease-causing Bmpr2 mutation were exposed to room air or to brief daily hyperoxia (95% oxygen for 3 hours) for 6 weeks and compared to wild-type animals with identical exposures. In both murine tissues and cultured endothelial cells, expression of mutant Bmpr2 was sufficient to cause oxidant injury that was particularly pronounced in mitochondrial membranes. With enhancement of mitochondrial generation of reactive oxygen species by hyperoxia, oxidant injury was substantially enhanced in mitochondrial membranes, even in tissues distant from the lung. Hyperoxia, despite its vasodilatory actions in the pulmonary circulation, significantly worsened the PAH phenotype (elevated RVSP, decreased cardiac output, increased pulmonary vascular occlusion) in Bmpr2 mutant animals. These studies demonstrate that oxidant injury and metabolic stress contribute directly to disease development and provide further evidence for PAH as a systemic disease with life-limiting cardiopulmonary manifestations.

PMID: 23742019

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