CD137 Signaling Promotes Endothelial Apoptosis by Inhibiting Nrf2 Pathway, and Upregulating NF-κB Pathway

Abstract

Background. Endothelial dysfunction and apoptosis resulting from oxidative stress can lead to the development of atherosclerosis. Our group has previously showed that CD137 signaling contributes to the progression of atherosclerosis and the vulnerability of plaques. The aim of this study is to investigate the effects of CD137 signaling in atherosclerosis on endothelial cells (ECs) apoptosis and to explore the underlying mechanisms. Methods. Serum samples were collected from 11 patients with acute myocardial infarction and 4 controls. Peritoneal injection of agonist-CD137 recombinant protein in ApoE−/− mice was used to determine whether CD137 signaling can promote apoptosis in vivo, and human umbilical vein endothelial cells treated with agonist-CD137 recombinant protein, M5580 (a Nrf2 pathway agonist) and CAPE (a NF-κB pathway inhibitor) were used to explore the effect of Nrf2 and NF-κB pathway in CD137 signaling-induced ECs apoptosis in vitro. Results. ELISA showed that Bcl-2 in the serum of AMI patients was lower than that of the control group, while TNF-α and sCD137 were higher than that of the control group. Confocal microscopy and Western blot analysis showed that the nuclear translocation of Nrf2 in the agonist-CD137 group was significantly inhibited, and the expression of its downstream antioxidant enzymes was also decreased when compared with control. Immunofluorescence and Western blot results showed that the nuclear translocation of NF-κB in the agonist-CD137 group was enhanced, and ELISA results showed that the secretion of proinflammatory cytokines in the agonist-CD137 group was increased. Immunofluorescence results revealed that ROS production in the agonist-CD137 group was higher than that in control, M5580 (a Nrf2 pathway agonist) and CAPE (a NF-κB pathway inhibitor) groups. In vitro studies using HUVECs and in vivo studies using high-fat-fed ApoE−/− mice showed that the number of apoptotic endothelial cells was the highest in the agonist-CD137 group. By contrast, both M5580 and CAPE treatments were able to reduce CD137 induced ECs apoptosis. Conclusions. Our results showed that CD137 signaling promotes ECs apoptosis through prooxidative and proinflammatory mechanisms, mediated by Nrf2 and NF-κB pathways, respectively.

Protective Effect of CD137 Deficiency against Post-infarction Cardiac Fibrosis and Adverse Cardiac Remodeling via ERK1/2 Signaling Pathways

“…Studies have suggested that CD137 can play a critical role in the development of atherosclerosis because our previous research has indicated that it can promote the formation of intraplaque calcification and neovascularization in atherosclerosis, leading to an increased risk of plaque rupture. [23][24][25][26][27][28][29][30] However, the role of CD137 in MI has not been clearly elucidated. Analysis of transcriptional data from myocardial fibroblasts isolated after MI indicates that CD137 is the primary inflammatory pathway activated on the first day after MI, suggesting that CD137 signaling activation on myocardial fibroblasts may play a role in the process of fibroblast phenotype transformation and MI.…”

Tanshinone IIA Has a Potential Therapeutic Effect on Kawasaki Disease and Suppresses Megakaryocytes in Rabbits With Immune Vasculitis

“…Several groups of genes that implicated in apoptosis, calcium regulation and cell cycle checkpoints were found and were validated using quantitative PCR. The most significantly up-regulated gene after tanshinone IIA treatment was TNF receptor superfamily member 9 (TNFRSF9, also known as CD137), which is primarily involved in apoptosis and inflammation ( 37 , 38 ). Research studies have shown that TNF-α, the receptor of which is a homologous to TNFRSF9, is able to induce two distinct caspase-8 activation pathways ( 39 ).…”

Contributions of Costimulatory Molecule CD137 in Endothelial Cells

“…Notably, reactive oxygen species upregulate proapoptotic proteins, such as Bax and cleaved caspase‐3, and downregulate antiapoptotic proteins, such as Bcl2, thereby inducing EC apoptosis. 25 The mechanism underlying the effects of CD137 signaling on human umbilical vein endothelial cells also includes the diacyl glycerol–PKC (protein kinase C) signaling pathway. Stimulation of human umbilical vein endothelial cells with anti‐CD137 antibody leads to the rapid formation of inositol triphosphate, which in turn upregulates diacyl glycerol levels and PKC activity and consequently results in the translocation of PKC from the cytosol to the plasma membrane.…”