S. Docosapentaenoic acid monoacylglyceride reduces inflammation and vascular remodeling in experimental pulmonary hypertension. Am J Physiol Heart Circ Physiol 307: H574 -H586, 2014. First published June 14, 2014 doi:10.1152/ajpheart.00814.2013 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 ϩ 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-B 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. docosapentaenoic acid; inflammation; pulmonary hypertension; nuclear factor-B; tumor necrosis factor-␣
Aims Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signaling and a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodeling in experimental RHD. Methods and Results Pulmonary hypertension (PH) and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting one day before MCT administration. Right-atrial (RA) conduction and gene-expression were analyzed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary-artery or right-ventricular remodeling. Nevertheless, in vivo transesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA-fibrosis but had no effect on RA-dilation. MCT increased RA-expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA-content of type-1 (proinflammatory) CD68-positive M1-macrophages without affecting type-2 (anti-inflammatory) M2-macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1-macrophages and increases in anti-inflammatory M2-macrophages versus MCT-only. MCT caused statistically-significant increases in protein-expression (Western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1 and CXCL2, and decreases in MMP2, versus control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. Conclusions The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA-remodeling, while suppressing inflammatory changes and fibrotic/electrical remodeling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodeling by suppressing ongoing inflammatory signaling. Translational perspective Mounting evidence suggests that chronic diseases are promoted by failure of inflammation to resolve. Here, we tested the effects of a molecule that promotes inflammation-resolution, Resolvin-D1, in a rat model of atrial arrhythmogenic remodeling caused by right-heart disease and marked by signs of persistent inflammatory signaling. Resolvin-D1 suppressed inflammatory signaling, shifted the balance of atrial macrophage-infiltration from proinflammatory M1-macrophages towards anti-inflammatory M2-macrophages and prevented atrial fibrosis. Disease-induced conduction-slowing was suppressed and atrial-fibrillation promotion was prevented. These findings support the potential value of a relatively non-toxic inflammation-resolving molecule in preventing the development of an arrhythmogenic substrate associated with chronic inflammatory signaling.
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.
monary 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 Ca 2ϩ sensitivity developed by HPAs that had been pretreated (or not) under proinflammatory conditions with either 10 ng/ml TNF-␣ 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-␣, IL-6, or endothelin-1 increased reactivity and Ca 2ϩ sensitivity of HPAs as revealed by agonist challenges with 80 mM KCl, 1 M serotonin (5-hydroxytryptamine), 30 nM U-46619, and 1 M phorbol 12,13-dibutyrate. However, 300 nM RvD1 as well as 1 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. pulmonary hypertension; docosapentanenoic acid monoacylglyceride; endothelin; resolvin D1; CPI-17; endothelin-1; tumor necrosis factor-␣; interleukin-6
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.