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Cyclooxygenase-2 inhibition and hypoxia-induced pulmonary hypertension: effects on pulmonary vascular remodeling and contractility.

Authors: Fredenburgh, LE  Ma, J  Perrella, MA 
Citation: Fredenburgh LE, etal., Trends Cardiovasc Med. 2009 Feb;19(2):31-7.
Pubmed: (View Article at PubMed) PMID:19577709
DOI: Full-text: DOI:10.1016/j.tcm.2009.04.003

Pulmonary arterial hypertension (PAH) is a significant disease process characterized by elevated pulmonary vascular resistance leading to increased right ventricular afterload and ultimately progressing to right ventricular dysfunction and often death. Irreversible remodeling of the pulmonary vasculature is the hallmark of pulmonary hypertension and frequently leads to progressive functional decline in patients with PAH despite treatment with currently available therapies. Metabolites of the arachidonic acid cascade play an important homeostatic role in the pulmonary vasculature, and dysregulation of pathways downstream of arachidonic acid plays a central role in the pathobiology of PAH. Cyclooxygenase-2 (COX-2) is up-regulated in pulmonary artery smooth muscle cells (PASMC) and inflammatory cells during hypoxia and plays a protective role in the lung's response to hypoxia. We recently demonstrated that absence of COX-2 was detrimental in a mouse model of hypoxia-induced pulmonary hypertension. Exposure of COX-2 null mice to hypoxia resulted in severe pulmonary hypertension characterized by enhanced pulmonary vascular remodeling and significant up-regulation of the endothelin-1 receptor ET(A)R in the lung after hypoxia. Absence of COX-2 in vitro led to enhanced contractility of PASMC after exposure to hypoxia, which could be attenuated by iloprost, a prostaglandin I(2) analog. These findings suggest that selective inhibition of COX-2 may have detrimental pulmonary vascular consequences in patients with preexisting pulmonary hypertension or underlying hypoxemic lung diseases. Here, we discuss our recent data demonstrating the adverse consequences of COX-2 inhibition on pulmonary vascular remodeling and PASMC contractility.


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CRRD Object Information
CRRD ID: 5135495
Created: 2011-07-25
Species: All species
Last Modified: 2011-07-25
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.