Activation of CD137 Signaling Promotes Angiogenesis in Atherosclerosis via Modulating Endothelial Smad1/5‐NFATc1 Pathway

Weng, Jiayi; Wang, Cuiping; Zhong, Wei; Li, Bo; Wang, Zhongqun; Shao, Chen; Yao, Chung-Chen Jane; Yan, Jinchuan

doi:10.1161/jaha.116.004756

Cited by 23 publications

(24 citation statements)

References 23 publications

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“…In our previous studies, CD137‐CD137L signalling has been shown to be involved in AS . We have also demonstrated that increased CD137 level may contribute to the instability of atherosclerotic lesion.…”

Section: Introductionmentioning

confidence: 62%

“…Emerging evidence has revealed that CD137‐CD137L signalling plays an important role in the plaque inflammation during AS development . However, it remains unclear whether EC‐derived exosomes participate in the Th17 cell differentiation, and if so, whether CD137‐CD137L signalling can regulate the immunoregulatory properties in AS development.…”

Section: Discussionmentioning

confidence: 99%

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Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

Geng

Zang

et al. 2020

J Cellular Molecular Medi

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| 4659 wileyonlinelibrary.com/journal/jcmm 1 | INTRODUC TI ON T helpers 17 (Th17) cells have been identified as a new subset of lymphocytes which are shown to promote atherosclerosis (AS), and their associated cytokines in the pathogenesis of AS appear to be contradictory at first glance. 1-3 Recently, growing attention has been paid to the relative contribution of the local vs. peripheral inflammation to the procession of AS. Here, we focused on the communication between peripheral inflammation and vascular inflammation of Th17 cell differentiation during AS.Exosomes are a subset of extracellular vesicles (EVs) released by almost all types of cells, and they play a significant role in cellular proliferation, apoptosis, stress response and differentiation in the initial stage and development of AS. 4,5 In the present study, we investigated exosome-mediated cell-to-cell communication, which induced Th17 cell differentiation and promoted progression of the atherosclerotic plaque. AbstractThe role of exosomes derived from endothelial cells (ECs) in the progression of atherosclerosis (AS) and inflammation remains largely unexplored. We aimed to investigate whether exosome derived from CD137-modified ECs (CD137-Exo) played a major role in AS and to elucidate the potential mechanism underlying the inflammatory effect. Exosomes derived from mouse brain microvascular ECs treated with agonist anti-CD137 antibody were used to explore the effect of CD137 signalling in AS and inflammation in vitro and vivo. CD137-Exo efficiently induced the progression of AS in ApoE −/− mice. CD137-Exo increased the proportion of Th17 cells both in vitro and vivo. The IL-6 contained in CD137-Exo which is regulated by Akt and NF-КB pathway was verified to activate Th17 cell differentiation. IL-17 increased apoptosis, inhibited cell viability and improved lactate dehydrogenase (LDH) release in ECs subjected to inflammation induced by lipopolysaccharide (LPS). The expression of soluble intercellular adhesion molecule1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1) and E-selectin in the supernatants of ECs after IL-17 treatment was dramatically increased. CD137-Exo promoted the progression of AS and Th17 cell differentiation via NF-КB pathway mediated IL-6 expression. This finding provided a potential method to prevent local and peripheral inflammation in AS. K E Y W O R D S atherosclerosis, endothelial cells; Th17 cells, exosomes

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Section: Introductionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

Geng

Zang

et al. 2020

J Cellular Molecular Medi

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“…The aortic ring assay is a well-accepted method for evaluating angiogenesis ( Gimenes et al, 2017 ; Weng et al, 2017 ): thoracic aortas were isolated, cut into rings, and used in the aortic ring assay as previously described. Microvessel sprouts began to merge at day 3 in aortic rings from mice treated with either NSD or HSD for consecutive 12 week.…”

Section: Resultsmentioning

confidence: 99%

Inflammasome-Independent NALP3 Contributes to High-Salt Induced Endothelial Dysfunction

Chen

et al. 2018

Front. Pharmacol.

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Backgrounds and Aims: Na+ is an important nutrient and its intake, mainly from salt (NaCl), is essential for normal physiological function. However, high salt intake may lead to vascular injury, independent of a rise in blood pressure (BP). Canonical NALP3 inflammasome activation is a caspase-1 medicated process, resulting in the secretion of IL-18 and IL-1β which lead to endothelial dysfunction. However, some researches uncovered a direct and inflammasome-independent role of NALP3 in renal injury. Thus, this study was designed to investigate the possible mechanisms of NALP3 in high salt induced endothelial dysfunction.Methods and Results: Changes in endothelial function were measured by investigating mice (C57BL/6J, NALP3-/- and wild-type, WT) fed with normal salt diet (NSD) or high salt diet (HSD) for 12W, and thoracic aortic rings from C57BL/6J mice cultured in high-salt medium. Changes of tube formation ability, intracellular reactive oxygen species (ROS), and NALP3 inflammasome expression were detected using mouse aortic endothelial cells (MAECs) cultured in high-salt medium. Consumption of HSD for 12W did not affect BP or body weight in C57BL/6J mice. Endothelium-dependent relaxation (EDR) decreased significantly in C57BL/6J mice fed with HSD for 12W, and in isolated thoracic aortic rings cultured in high-salt medium for 24 h. Results from the aortic ring assay also revealed that the angiogenic function of thoracic aortas was impaired by either consumption of HSD or exposure to high-salt medium. NALP3-/- mice fed with HSD showed a relatively mild decrease in EDR function when compared with WT mice. Tube length of thoracic aortic rings from NALP3-/- mice was longer than those from WT mice after receiving high-salt treatment. Inhibiting NALP3 with a NALP3 antagonist, small interfering (si) RNA experiments using si-NALP3, and decomposing ROS significantly improved tube formation ability in MAECs under high salt medium. NALP3 expression was increased in MAECs cultured with high salt treatment and inhibiting NALP3 reversed the down-regulation of p-eNOS induced by high salt in MAECs.Conclusion: High salt intake impairs endothelial function, which is at least in part mediated by increasing NALP3 expression.

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“…Angiogenesis is an important factor that influences the development of atherosclerotic plaques and is closely associated with local neovascularization and plaque stability ( 1 ). It has been demonstrated that excessive angiogenesis is associated with intraplaque hemorrhage, suggesting that neovascularization may contribute to lesion progression and rupture ( 2 ). Rupture-prone vulnerable plaques exhibit high lipid infiltration, increased numbers of inflammatory cells, a thin fibrous cap, and extensive endometrial and adventitial neovascularization ( 3 – 5 ).…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA TCONS_00024652 regulates vascular endothelial cell proliferation and angiogenesis via microRNA‑21

et al. 2018

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Acute coronary syndrome caused by the rupture of atherosclerotic plaques is one of the primary causes of major cardiovascular events, and neovascularization within the plaque is closely associated with its stability. Long noncoding RNA (lncRNAs) is a type of noncoding RNA that serves a crucial role in regulating vascular endothelial cells (VECs). The aim of the present study was to investigate the effect of lncRNA TCONS_00024652 on the proliferation and angiogenesis of VECs following stimulation with TNF-α. The expression of lncRNA and miRNA was measured in human umbilical vein endothelial cells (HUVECs) by reverse transcription-quantitative polymerase chain reaction. Cell proliferation was measured using a Cell Counting Kit-8 assay. Wound healing and tube formation assays were performed to determine cell migration and angiogenesis. Interactions between TCONS_00024652 and miR-21 were determined using bioinformatics and a dual-luciferase reporter assay. The results demonstrated that TCONS_00024652 is highly expressed in TNF-α-induced HUVECs. Functional assays demonstrated that the dysregulated expression of TCONS_00024652 promotes endothelial cell proliferation and angiogenesis, whereas TCONS_00024652 knockdown induces the opposite effects. Bioinformatics analysis using starBase predicted putative binding at the 3′-untranslated region of TCONS_00024652 and miR-21 and luciferase reporter assays further verified this interaction. The results of the present study suggest that the targeting of TCONS_00024652 by miR-21 may be a potential method of improving vascular endothelial dysfunction, neovascularization maturation and plaque stabilization.

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Activation of CD137 Signaling Promotes Angiogenesis in Atherosclerosis via Modulating Endothelial Smad1/5‐NFATc1 Pathway

Cited by 23 publications

References 23 publications

Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

Inflammasome-Independent NALP3 Contributes to High-Salt Induced Endothelial Dysfunction

Long noncoding RNA TCONS_00024652 regulates vascular endothelial cell proliferation and angiogenesis via microRNA‑21

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