Montreal Heart Institute
Montreal, Quebec | Canada
Main Specialties: Cardiovascular Disease
Additional Specialties: Physiology, Pharmacology, Cell and Molecular Biology, Biophysics, Cardiovascular Diseases, Cardiac Electrophysiology, Lung diseases, Pulmonary Hypertension Inflammation
Post-Doctorate in Cardiology
Montreal Heart Institute
5000 Belanger Street
Montreal, Qc, H1T 1C8
Primary Affiliation: Montreal Heart Institute - Montreal, Quebec , Canada
Pharmacol Res Perspect. 2016 Oct 18;4(6):e00263
Pharmacology Research and Perspectives
Bronchial inflammation contributes to a sustained elevation of airway hyperresponsiveness (AHR) in asthma. Conversely, omega‐3 fatty acid derivatives have been shown to resolve inflammation in various tissues. Thus, the effects of docosapentaenoic acid monoacylglyceride (MAG‐DPA) were assessed on inflammatory markers and reactivity of human distal bronchi as well as in a cultured model of guinea pig tracheal rings. Human bronchi were dissected and cultured for 48 h with 10 ng/mL TNF‐α or IL‐13. Guinea pig tracheas were maintained in organ culture for 72 h which was previously shown to trigger spontaneous AHR. All tissues were treated with increasing concentrations of MAG‐DPA (0.1, 0.3, and 1 μmol/L). Pharmacomechanical reactivity, Ca2+ sensitivity, and western blot analysis for specific phosphoproteins and transcription factors were performed to assess the effects of both cytokines, alone or in combination with MAG‐DPA, on human and guinea pig airway preparations. Although 0.1 μmol/L MAG‐DPA did not significantly reduce inflammatory biomarkers, the higher concentrations of MAG‐DPA (0.3 and 1 μmol/L) blunted the activation of the TNF‐α/NF κB pathway and abolished COX‐2 expression in human and guinea pig tissues. Moreover, 0.3 and 1 μmol/L MAG‐DPA consistently decreased the Ca2+ sensitivity and pharmacological reactivity of cultured bronchial explants. Furthermore, in human bronchi, IL‐13‐stimulated phosphorylation of CPI‐17 was reversed by 1 μmol/L MAG‐DPA. This effect was further amplified in the presence of 100 μmol/L aspirin. MAG‐DPA mediates antiphlogistic effects by increasing the resolution of inflammation, while resetting Ca2+ sensitivity and contractile reactivity.
Hiram R, Morin C, Fortin S, Rousseau E (2016) MAG-DHA, precursor of D-series resolvins, induces powerful resolution of various components of pulmonary hypertension induced by monocrotaline in rats. Pulm Crit Care Med 1: doi: 10.15761/PCCM.1000108
Pulmonary Critical Care Medicine
Pulmonary hypertension (PH) is a disease of the lung vessels involving abnormal vasoconstriction which limits lung blood circulation and oxygenation. Despite current pharmacological treatments, PH still remains associated with high morbidity. Our hypothesis is that systemic lung inflammation may be resolved via relevant treatment in a rat model of Monocrotaline (MCT)-induced PH. The goal of the study was to assess the resolving effects of monoacylglyceride docosahexaenoic acid (MAG-DHA) on MCT-induced PH by measuring inflammation biomarkers and contractility levels in pulmonary arteries. Experimental rats were administered 60 mg/kg of MCT on day 1 and subsequently treated from day 14 onward with 231 mg/kg MAG-DHA daily for 7 days and compared with non-treated MCT animals and untreated controls. Results show that MAG-DHA normalized right ventricle (RV) weight which was significantly increased in the MCT-treated group compared to controls. Mean artery wall thickness increased from 12 µm in control rats to 48 µm in MCT rats while MAG-DHA treatment significantly curbed this increase with a resulting wall thickness of 20 µm. MCT rats also displayed increased arterial reactivity in response to 30 nM U-46619 (thromboxane A2 analog) and 1 µM PDBu (a potent PKC activator), whereas MAG-DHA treatment significantly decreased this pharmacological hyper-responsiveness. Western blot analysis confirmed that MCT treatment increased the phosphorylation levels of P-CPI-17 and P-MYPT-1, which were largely reversed after MAG-DHA treatment. Lastly, under MCT condition, a large array of inflammatory biomarkers were enhanced, including TNF-α, COX-2, STAT-3 as well as the phosphorylated nuclear factors P-C-Fos, P-C-Jun and P-NF-κB, with MAG-DHA treatment strongly reversing this inflammatory profile. In conclusion, a 7-day treatment with MAG-DHA is able to resolve the inflammatory status in a rat PH model.
Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L776-88
American Journal of Physiology Lung Cellular and Molecular Physiology.
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.
Am J Physiol Heart Circ Physiol. 2014 Dec 1;307(11):H1547-58
American Journal of Physiology and Heart Circulation 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 endothelin-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 mM KCl, 1 μM serotonin (5-hydroxytryptamine), 30 nM U-46619, and 1 μM 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.
Am J Physiol Heart Circ Physiol. 2014 Aug 15;307(4):H574-86
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.