title: Resolvin E1 normalizes contractility, Ca2+ sensitivity and smooth muscle cell migration rate in TNF-α- and IL-6-pretreated human pulmonary arteries.
abstract: Pulmonary hypertension (PH) is a rare disease in which pathophysiology is characterized by an increase in proinflammatory mediators, chronic endothelial dysfunctions, and a high migration rate of smooth muscle cells (SMC). Over the course of the last decade, various treatments have been proposed to relax the pulmonary arteries, none of which have been effective in resolving PH. Our hypothesis is that artery-relaxing drugs are not the long-term solution, but rather the inhibition of tissue inflammation, which underlies human pulmonary artery (HPA) dysfunctions that lead to abnormal vasoconstriction. The goal of the present study was to assess the anti-inflammatory effects of resolvin E1 (RvE1) with concomitant effects on SMC migration and on HPA reactivity. The role and mode of action of RvE1 and its precursor, monoacylglyceride eicosapentaenoic acid were assessed on HPA under proinflammatory conditions, involving a combined pretreatment with 10 ng/ml TNF-α and 10 ng/ml IL-6. Our results show that TNF-α and IL-6 treatment induced hyperreactivity and Ca(2+) hypersensitivity in response to pharmaco-mechanical stimuli, including 80 mM KCl, 1 μM phorbol 12-13-dibutyrate, and 30 nM U-46619. Furthermore, the proinflammatory treatment increased the migration rate of SMC isolated from HPA. The phosphorylation level of regulatory contractile proteins (CPI-17, MYPT-1), and proinflammatory signaling pathways (c-Fos, c-Jun, NF-κB) were also significantly increased compared with control conditions. Conversely, 300 nM RvE1 was able to normalize all of the above abnormal events triggered by proinflammation. In conclusion, RvE1 can resolve human arterial hyperreactivity via the resolution of inflammatory markers.
authors: Department of Pharmacology and Physiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada;
authors: Roddy
authors: R
authors: Hiram
authors: Department of Pathology, Université de Sherbrooke, Sherbrooke, Quebec, Canada;
authors: Edmond
authors: E
authors: Rizcallah
authors: Department of Pathology, Université de Sherbrooke, Sherbrooke, Quebec, Canada;
authors: Sofia
authors: S
authors: Marouan
authors: Service of Thoracic Surgery, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; and.
authors: Chantal
authors: C
authors: Sirois
authors: Service of Thoracic Surgery, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; and.
authors: Marco
authors: M
authors: Sirois
authors: Department of Pharmacology and Physiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada; SCF Pharma, Ste-Luce, Quebec, Canada.
authors: Caroline
authors: C
authors: Morin
authors: SCF Pharma, Ste-Luce, Quebec, Canada.
authors: Samuel
authors: S
authors: Fortin
authors: Department of Obstetrics-Gynecology, Université de Sherbrooke, Sherbrooke, Quebec, Canada; Eric.Rousseau@USherbrooke.ca.
authors: Eric
authors: E
authors: Rousseau
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008954:Models, Biological; D050178:Monoglycerides / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D002722:Chlorobenzenes
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D002118:Calcium; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D007211:Indoles; D018836:Inflammation Mediators; D015850:Interleukin-6; D016859:Lipoxygenase Inhibitors; D020780:Matrix Metalloproteinase 9; D050178:Monoglycerides; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C588285:1-eicosapentaenoylglycerol; C508600:IL6 protein, human; C467484:VEGFA protein, human; C518399:resolvin D1; C060893:MK-886; D002722:Chlorobenzenes; C579270:MMP9 protein, human; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid
keywords: CPI-17; NF-κB; RVD1; RVE1; overreactivity; pulmonary hypertension