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.

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

“…Attenuation of VSMC migration by SPMs (ATL, RvD1, RvD2, RvE1, MaR1) has been a consistent finding in vitro , both with VSMC harvested from human saphenous veins (Ho, Spite et al 2010) (Miyahara, Runge et al 2013) and with arterial VSMC harvested from rodent aortas (Akagi, Chen et al 2015) (Petri, Laguna-Fernandez et al 2015, Wu, Mottola et al 2017) as well as human pulmonary arteries (Hiram, Rizcallah et al 2015). This effect has been demonstrated across several prototypic VSMC motogens including PDGF, thrombin, angiotensin II, TNF-α and IL-6 (Hiram, Rizcallah et al 2015, Mottola, Wu et al 2017, Wu, Mottola et al 2017). Associated with this effect, resolvins induce rapid and reversible changes in VSMC cell-shape with a decreased length:width ratio corresponding to an anti-migratory phenotype (Ho, Spite et al 2010, Miyahara, Runge et al 2013, Mottola, Wu et al 2017, Wu, Mottola et al 2017).…”

TNFαAffects Ciliary Beat Response to Increased Viscosity in Human Pediatric Airway Epithelium

“…In airway smooth muscle cells, it has been shown that TNF α increased [Ca 2+ ] i by modifying mitochondrial calcium concentration [38], decreasing the expression of Ca 2+ -ATPase, and slowing Ca 2+ reuptake [39]. Furthermore, it has been demonstrated that TNF α induced the upregulation of protein kinase pathways leading to an increment in Ca 2+ sensitivity [40]. Our results suggest that the increase in [Ca 2+ ] i observed after TNF α incubation could protect cells from a worse cilia slowing and the recovery of CBF to basal ciliary activity, after viscous loading.…”

MAG-DHA, Precursor of D-Series Resolvins, Induces Powerful Resolution of Various Components of Pulmonary Hypertension Induced By Monocrotaline in Rats

“…MAG-DHA is neutral lipid which is very well absorbed by tissues [29] and becomes a DHA donor upon the action of MAG-lipase and the precursor of several omega-3 derivatives such as resolvins and protectins upon the action of 15-LOX and 5-LOX [10]. Resolvins have been reported to reduce pro-inflammatory markers [17,30], namely TNFα and IL-1β, and to prevent systemic hypertension in rats [31]. Furthermore, RvD1, A trihydroxylated DHA derivative has recently been reported to reverse the pharmacological reactivity and Ca 2+ sensitivity induced by ET-1 and IL-6 in human pulmonary artery [17].…”