Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 307, Issue 11, Pages H1547-H1558Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00452.2014
Keywords
pulmonary hypertension; docosapentanenoic acid monoacylglyceride; endothelin; resolvin D1; CPI-17; endothelin-1; tumor necrosis factor-alpha; interleukin-6
Funding
- Heart and Stroke Foundation of Canada/Quebec
- Health Respiratory Training Program of Quebec
- Canadian Institutes of Health Research
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Pulmonary hypertension (PH) is a rare and progressive disease characterized by an inflammatory status and vessel wall remodeling, resulting in increased pulmonary artery resistance. During the last decade, treatments have been proposed; most of them target the endothelial pathways that stimulate smooth muscle cell relaxation. However, PH remains associated with significant morbidity. We hypothesized that inflammation plays a crucial role in the severity of the abnormal vasoconstriction in PH. The goal of this study was to assess the effects of resolvin D1 (RvD1), a potent anti-inflammatory agent, on the pharmacological reactivity of human pulmonary arteries (HPAs) via an in vitro model of induced hyperreactivity. The effects of RvD1 and monoacylglyceride compounds were measured on contractile activity and Ca2+ sensitivity developed by HPAs that had been pretreated (or not) under proinflammatory conditions with either 10 ng/ml TNF-alpha or 10 ng/ml IL-6 or under hyperreactive conditions with 5 nM endothelin- 1. The results demonstrated that, compared with controls, 24-h pretreatment with TNF-alpha, IL-6, or endothelin-1 increased reactivity and Ca2+ sensitivity of HPAs as revealed by agonist challenges with 80 mM KCl, 1 mu M serotonin (5-hydroxytryptamine), 30 nM U-46619, and 1 mu M phorbol 12,13-dibutyrate. However, 300 nM RvD1 as well as 1 mu M monoacylglyceride-docosapentaenoic acid monoglyceride strongly reversed the overresponsiveness induced by both proinflammatory and hyperreactive treatments. In pretreated pulmonary artery smooth muscle cells, Western blot analyses revealed that RvD1 treatment decreased the phosphorylation level of CPI-17 and expression of transmembrane protein member 16A while increasing the detection of G protein-coupled receptor 32. The present data demonstrate that RvD1, a trihydroxylated docosahexaenoic acid derivative, decreases induced overreactivity in HPAs via a reduction in CPI-17 phosphorylation and transmembrane protein member 16A expression.
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