Matrine‐Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species‐Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling

Abstract

BackgroundThe matrine‐type alkaloids are bioactive components extracted from Sophora flavescens, which is used in treatment of diabetes mellitus in traditional Chinese medicine. Advanced glycation end products mediate diabetic vascular complications. This study was aimed to investigate the protective effects and molecular mechanisms of matrine‐type alkaloids on advanced glycation end products–induced reactive oxygen species–mediated endothelial apoptosis.Methods and ResultsRats aorta and cultured rat aortic endothelial cells were exposed to advanced glycation end products. Matrine‐type alkaloids, p38 mitogen‐activated protein kinase (MAPK) inhibitor, and small interference RNAs against p38 MAPK kinases MAPK kinase kinase (MKK)3 and MKK6 were administrated. Intracellular reactive oxygen species production, cell apoptosis, phosphorylation of MKKs/p38 MAPK, and expression levels of heme oxygenase/NADPH quinone oxidoreductase were assessed. The nuclear factor erythroid 2‐related factor 2 nuclear translocation and the binding activity of nuclear factor erythroid 2‐related factor 2 with antioxidant response element were also evaluated. Matrine‐type alkaloids suppressed intracellular reactive oxygen species production and inhibited endothelial cell apoptosis in vivo and in vitro by recovering phosphorylation of MKK3/6 and p38 MAPK, nuclear factor erythroid 2‐related factor 2 nuclear translocation, and antioxidant response element binding activity, as well as the expression levels of heme oxygenase/NADPH quinone oxidoreductase. p38 MAPK inhibitor treatment impaired the effects of matrine‐type alkaloids in vivo and in vitro. MKK3/6 silencing impaired the effects of matrine‐type alkaloids in vitro.ConclusionsMatrine‐type alkaloids exert endothelial protective effects against advanced glycation end products induced reactive oxygen species–mediated apoptosis by targeting MKK3/6 and enhancing their phosphorylation.

Vascular smooth muscle-MAPK14 is required for neointimal hyperplasia by suppressing VSMC differentiation and inducing proliferation and inflammation

“…This suggests that MAPK14 might be dispensable for vascular development. In agreement with this notion, although there has been an overwhelming amount of evidence supporting critical roles of MAPK14 in EC pathologies [61], [62], depleting MAPK14 in endothelial cells using Tie2-Cre driver does not lead to any defect in vasculature in mice at baseline [16]. Our current study showed that induced loss of MAPK14 in mature VSMCs failed to impact adult vasculature homeostasis but exhibited strong protection from injury-induced neointima formation.…”

A Systematic Review of the Pharmacology, Toxicology and Pharmacokinetics of Matrine

“…In the middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia-reperfusion (I/R) injury model, MT pretreatment for 7 consecutive days effectively decreased Bax and, caspase-3 expressions, and reduced MDA levels, while it up-regulated Bcl-2, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC), thereby attenuating MCAO-induced cerebral I/R injury ( Zhao et al., 2015 ). In addition, MT markedly increased the expression levels of antioxidant enzymes such as NADPH quinone oxidoreductase-1(NQO-1) and heme oxygenase-1(HO-1), and decreased AGEs-induced ROS production through activation of the p38 mitogen-activated protein kinase/nuclear factor E2-related factor-2/antioxidant response elements (MAPK/Nrf2/ARE) antioxidant signaling pathway ( Liu et al., 2017a ). In a D-galactose- (D-gal-) induced aging mouse model, Sun et al.…”

Resveratrol Attenuates Cognitive Deficits of Traumatic Brain Injury by Activating p38 Signaling in the Brain

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