贺婷
中国医学科学院阜外医院 动物实验中心
INTRODUCTION:Glucose-induced insulin resistance is a typical character of diabetes. Nicorandil is now widely used in ischemic heart disease. Nicorandil shows protective effects against oxidative and endoplasmic reticulum (ER) stress, which are involved in insulin resistance. Here, we investigated mechanisms of nicorandil's novel pharmacological activity on insulin resistance in diabetes.RESEARCH DESIGN AND METHODS:Nicorandil was administrated to streptozotocin-induced animals with diabetes and high glucose exposed skeletal muscle cells. Insulin resistance and glucose tolerance were evaluated. Molecular mechanisms concerning oxidative stress, ER stress signaling activation and glucose uptake were assessed.RESULTS:Nicorandil attenuated high glucose-induced insulin resistance without affecting fasting blood glucose and glucose tolerance in whole body and skeletal muscle in rats with diabetes. Nicorandil treatment suppressed protein kinase C/nicotinamide adenine dinucleotide phosphate oxidases system activities by reducing cytoplasmic free calcium level in skeletal muscle cells exposed to high glucose. As a result, the oxidative stress-mediated ER stress protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α/activating transcription factor 4/CEBP homologous protein/tribbles homolog (TRB)3 signaling pathway activation was inhibited. Nicorandil downregulated expression of TRB3 and thus facilitated Akt phosphorylation in response to insulin stimulation, leading to glucose transporter4 plasma membrane translocation which promoted glucose uptake capability of skeletal muscle cells.CONCLUSIONS:By reducing cytoplasmic calcium, nicorandil alleviated high glucose-induced insulin resistance by inhibiting oxidative stress-mediated ER stress PERK pathway.
BMJ open diabetes research & care 2021
Background: Factor Xa (FXa) is a mediator initiating and accelerating atherosclerosis (AS). Both macrophage and vascular smooth muscle cells (VSMCs) participate in AS progression. This study was aimed to investigate the mechanisms underlying the effects of the FXa inhibitor rivaroxaban on AS. Methods: Rivaroxaban was administered to AS mice. Primary macrophages were exposed to FXa, treated with rivaroxaban, and transfected with siRNA silencing protease-activated receptor 2 (PAR2), hypoxia-inducible factor 1α (HIF1α), delta-like receptor 4 (Dll4), and Akt. Interaction between macrophages and VSMCs was assessed by co-culturing systems. Atherosclerotic lesions were evaluated by oil red O stain. Fluorescent staining was used to determine the cell phenotypes. Secretions of inflammatory cytokines and collagen were assessed by ELISA and Sircol assays. Western blotting was used to evaluate the protein expression and phosphorylation levels. Results: Rivaroxaban reduced lesion area, accumulation of M1 macrophages, and contractile-synthetic phenotypic conversion of VSMCs in atherosclerotic plaques. FXa exposure induced polarization of macrophages toward M1 and Dll4 high expression, which were inhibited by PAR2, Akt1, and HIF1α silencing. Rivaroxaban treatment inhibited PAR2/Akt/HIF1α signaling activation and Dll4 expression in FXa-exposed macrophages. By cell-to-cell contact, M1 macrophages induced Notch signaling activation in VSMCs which committed contractile-synthetic conversion. Rivaroxaban treatment and Dll4 silencing incapacitated macrophage in inducing phenotypic conversion of VSMCs upon cell-to-cell contact. Conclusion: Rivaroxaban suppresses AS by inhibiting FXa-induced PAR2/Akt/HIF1α signaling activation-mediated macrophage M1 polarization and high Dll4 expression. These macrophages facilitated VSMCs to perform contractile-synthetic phenotypic conversion upon macrophage-VSMCs cell-to-cell contact.
Frontiers in cardiovascular medicine 2021
