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Hiram R.,Universite de Sherbrooke | Rizcallah E.,Universite de Sherbrooke | Sirois C.,Universite de Sherbrooke | Sirois M.,Universite de Sherbrooke | And 3 more authors.
American Journal of Physiology - Heart and Circulatory Physiology

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-α or 10 ng/ml IL-6 or under hyperreactive conditions with 5 nM endothe-lin-1. The results demonstrated that, compared with controls, 24-h pretreatment with TNF-α, IL-6, or endothelin-1 increased reactivity and Ca2+ sensitivity of HPAs as revealed by agonist challenges with 80 μM KCl, 1 (μM serotonin (5-hydroxytryptamine), 30 nM U-46619, and 1 (αM phorbol 12,13-dibutyrate. However, 300 nM RvD1 as well as 1 (μM 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. © 2014 the American Physiological Society. Source

Morin C.,SCF Pharma | Morin C.,Universite de Sherbrooke | Blier P.U.,University of Quebec at Rimouski | Fortin S.,SCF Pharma | Fortin S.,University of Quebec at Rimouski
Arthritis Research and Therapy

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines and eicosanoids involved in RA pathogenesis. The aim of this study was to determine the therapeutic potential of ω3 monoglyceride (MAG-ω3) compounds in an in vivo rat model of RA induced by Complete Freund's Adjuvant (CFA). Method: CFA rats were untreated or treated per os with three specific compounds, namely, MAG-docosahexaenoic acid (MAG-DHA), MAG-eicosapentaenoic acid (MAG-EPA) and MAG-docosapentaenoic acid (MAG-DPA). Morphological and histological analyses, as well as pro-inflammatory marker levels were determined following MAG-ω3 treatments. Results: Morphological and histological analyses revealed that MAG-EPA and MAG-DPA exhibited strong activity in reducing the progression and severity of arthritic disease in CFA rats. Following MAG-EPA and MAG-DPA treatments, plasma levels of the pro-inflammatory cytokines; interleukin 17A (IL-17A), IL-1β, IL-6 and tumor necrosis factor aα (TNFaα) were markedly lower when compared to CFA-untreated rats. Results also revealed a decreased activation of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor-kappa B (NFΚB) pathways correlated with a reduced expression of TNFaα, cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2) and MMP-9 in paw homogenates derived from MAG-EPA and MAG-DPA-treated rats. Of interest, the combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in CFA rats. Conclusion: Altogether, the present data suggest that MAG-EPA, without vitamin E, represents a new potential therapeutic strategy for resolving inflammation in arthritis. © 2015 Morin et al. Source

Morin C.,SCF Pharma | Fortin S.,SCF Pharma | Cantin A.M.,Universite de Sherbrooke
Clinical and Experimental Allergy

Background: Asthma is a chronic disease characterized by airways hyperresponsiveness, inflammation and airways remodelling involving reversible bronchial obstruction. Omega-3 fatty acids and their derivatives are known to reduce inflammation in several tissues including lung. Objectives: The effects of eicosapentaenoic acid monoacylglyceride (MAG-EPA), a newly synthesized EPA derivative, were determined on the resolution of lung inflammation and airway hyperresponsiveness in an in vivo model of allergic asthma. Methods: Ovalbumin (OVA)-sensitized guinea-pigs were treated or not with MAG-EPA administered per os. Isometric tension measurements, histological analyses, homogenate preparation for Western blot experiments or total RNA extraction for RT-PCR were performed to assess the effect of MAG-EPA treatments. Results: Mechanical tension measurements revealed that oral MAG-EPA treatments reduced methacholine (MCh)-induced bronchial hyperresponsiveness in OVA-sensitized guinea-pigs. Moreover, MAG-EPA treatments also decreased Ca2+ hypersensitivity of bronchial smooth muscle. Histological analyses and leucocyte counts in bronchoalveolar lavages revealed that oral MAG-EPA treatments led to less inflammatory cell recruitment in the lung of OVA-sensitized guinea-pigs when compared with lungs from control animals. Results also revealed a reduction in mucin production and MUC5AC expression level in OVA-sensitized animals treated with MAG-EPA. Following MAG-EPA treatments, the transcript levels of pro-inflammatory markers such as IL-5, eotaxin, IL-13 and IL-4 were markedly reduced. Moreover, per os MAG-EPA administrations reduced COX2 over-expression in OVA-sensitized animals. Conclusion and Clinical Relevance: We demonstrate that MAG-EPA reduces airway hyperresponsiveness and lung inflammation in OVA-sensitized animals, a finding consistent with a decrease in IL-4, IL-5, IL-13, COX-2 and MUC5AC expression levels in the lung. The present data suggest that MAG-EPA represents a new potential therapeutic strategy for resolving inflammation in allergic asthma. © 2013 John Wiley & Sons Ltd. Source

Morin C.,SCF Pharma | Morin C.,Universite de Sherbrooke | Rousseau E.,Universite de Sherbrooke | Blier P.U.,University of Quebec at Rimouski | And 2 more authors.
American Journal of Physiology - Heart and Circulatory Physiology

ω-3 Fatty acid supplementation has been associated with lower blood pressure. Cardiovascular diseases are also known to be linked directly to an increase in ω-6 and a reduction in ω-3 fatty acid levels in blood circulation and tissues. To determine the effect of docosahexaenoic acid monoglycerides (MAG-DHA) on blood pressure, lipid profiles, and vascular remodeling in rats fed a high-fat/high-carbohydrate (HFHC) diet. Studies were performed in male rats subjected to 8 wk of HFHC diet supplemented or not with 3 g/day MAG-DHA. After 8 wk of daily MAG-DHA treatment, rats in the HFHC + MAG-DHA group had lower arterial blood pressure and heart rate compared with the HFHC group. Moreover, MAG-DHA prevented the increase aortic wall thickness, whereas lipid analysis of aortic tissues revealed an increase in DHA/AA ratio correlated with the production of resolvin D2 and D3 metabolites. Histological analysis revealed that MAG-DHA prevented the development of LVH in the HFHC group. Serum lipid profile analysis further showed a decrease in total cholesterol (TC) and LDL, including very low-density lipoprotein (VLDL) and triglyceride (TG) levels, together with an increase in HDL levels after 8 wk of MAG-DHA treatment compared with the HFHC group. Furthermore, daily MAG-DHA treatment resulted in reduced proinflammatory marker levels such as CRP, IL-6, TNFα, and IL-1β. Altogether, these findings revealed that per os administration of MAG-DHA prevents HFHC-diet induced hypertension and LVH in rats. © 2015 the American Physiological Society. Source

Morin C.,SCF Pharma | Morin C.,Universite de Sherbrooke | Hiram R.,Universite de Sherbrooke | Rousseau E.,Universite de Sherbrooke | And 3 more authors.
American Journal of Physiology - Heart and Circulatory Physiology

n-3 Polyunsaturated fatty acids (n-3 PUFA) have been shown to reduce inflammation and proliferation of pulmonary artery smooth muscle cells under pathophysiological conditions. However, the anti-inflammatory effect of the newly synthesized docosapentaenoic acid monoacylglyceride (MAG-DPA) on key signaling pathways in pulmonary hypertension (PH) pathogenesis has yet to be assessed. The aim of the present study was to determine the effects of MAG-DPA on pulmonary inflammation and remodeling occurring in a rat model of PH, induced by a single injection of monocrotaline (MCT: 60 mg/kg). Our results demonstrate that MAG-DPA treatment for 3 wk following MCT injection resulted in a significant improvement of right ventricular hypertrophy (RVH) and a reduction in Fulton's Index (FI). Morphometric analyses revealed that the wall thickness of pulmonary arterioles was significantly lower in MCT + MAG-DPA-treated rats compared with controls. This result was further correlated with a decrease in Ki-67 immunostaining. Following MAG-DPA treatments, lipid analysis showed a consistent increase in DPA together with lower levels of arachidonic acid (AA), as measured in blood and tissue samples. Furthermore, in MCT-treated rats, oral administration of MAG-DPA decreased NF-κB and p38 MAPK activation, leading to a reduction in MMP-2, MMP-9, and VEGF expression levels in lung tissue homogenates. Altogether, these data provide new evidence regarding the mode of action of MAG-DPA in the prevention of pulmonary hypertension induced by MCT. © 2014 the American Physiological Society. Source

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