AMP-dependent Kinase Inhibits Oxidative Stress-induced Caveolin-1 Phosphorylation and Endocytosis by Suppressing the Dissociation between c-Abl and Prdx1 Proteins in Endothelial Cells

Takeuchi, K.; Morizane, Yuki; Kamami-Levy, Cynthia; Suzuki, Jun; Kayama, Maki; Cai, Wenyi; Miller, Joan W.; Vavvas, Demetrios G.

doi:10.1074/jbc.m113.460832

Cited by 38 publications

(32 citation statements)

References 54 publications

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“…This study showed that H 2 O 2 exposure induced the phosphorylation of Cav-1, which resulted in endothelial barrier disruption [19]. Further research also confirmed the induction of Cav-1 following oxidative stress and the fundamental role of Cav-1 in endothelial barrier function [20]. It also has been shown that caveolae and Cav-1 may play an important role in the mediation of native and modified LDL uptake/efflux and transcytotic trafficking in ECs [21].…”

Section: Discussionmentioning

confidence: 92%

Effects of selenoprotein S on oxidative injury in human endothelial cells

Zhao

Men

et al. 2013

J Transl Med

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BackgroundSelenoprotein S (SelS) is an important endoplasmic reticulum and plasma membrane-located selenoprotein implicated in inflammatory responses and insulin resistance. However, the effects of SelS on endothelial cells (ECs) have not been reported. In the present study, the role of SelS in oxidative stress and the underlying mechanism were investigated in human ECs.MethodsA SelS over-expression plasmid (pc-SelS) and a SelS-siRNA plasmid were transfected into human umbilical vein endothelial cells (American Type Culture Collection, USA). The cells were divided into four groups: control, SelS over-expression (transfected with pc-SelS), vector control, and SelS knockdown (transfected with siRNA-SelS). After treating the cells with H2O2, the effects of oxidative stress and the expression of caveolin-1 (Cav-1) and protein kinase Cα (PKCα) were investigated.ResultsFollowing treatment with H2O2, over-expression of SelS significantly increased cell viability and superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) production and Cav-1 gene and protein expression. However, no effects on PKCα were observed. In contrast, knockdown of SelS significantly decreased cell viability, SOD activity, and PKCα gene and protein expression, and increased MDA production and Cav-1 gene and protein expression.ConclusionsSelS protects ECs from oxidative stress by inhibiting the expression of Cav-1 and PKCα.

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Section: Discussionmentioning

confidence: 92%

Effects of selenoprotein S on oxidative injury in human endothelial cells

Zhao

Men

et al. 2013

J Transl Med

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“…Previous studies have shown that AMPK participates in regulation of angiogenesis and function of endothelial cells [18, 19]. However, the precise role of AMPK in this aspect is rather controversial.…”

Section: Introductionmentioning

confidence: 99%

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

et al. 2017

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Anti-VEGF therapy has been proven to be effective in the treatment of pathological angiogenesis. However, therapy resistance often occurs, leading to development of alternative approaches. The present study examines if AMPK negatively regulates ALK1-mediated signaling events and associated angiogenesis. Thus, we treated human umbilical vein endothelial cells with metformin as well as other pharmacological AMPK activators and showed that activation of AMPK inhibited Smad1/5 phosphorylation and tube formation induced by BMP9. This event was mimicked by expression of the active mutant of AMPKα1 and prevented by the dominant negative AMPKα1. Metformin inhibition of BMP9 signaling is possibly mediated by upregulation of Smurf1, leading to degradation of ALK1. Furthermore, metformin suppressed BMP9-induced angiogenesis in mouse matrigel plug. In addition, laser photocoagulation was employed to evaluate the effect of metformin. The data revealed that metformin significantly reduced choroidal neovascularization to a level comparable to LDN212854, an ALK1 specific inhibitor. In conjunction, metformin diminished expression of ALK1 in endothelium of the lesion area. Collectively, our study for the first time demonstrates that AMPK inhibits ALK1 and associated angiogenesis/neovascularization. This may offer us a new avenue for the treatment of related diseases using clinically used pharmacological AMPK activators like metformin in combination with other strategies to enhance the treatment efficacy or in the case of anti-VEGF resistance.

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“…Several regulatory mechanisms of Cav-1 phosphorylation have been identified. Under oxidative stress, AMPK inhibits Cav-1 phosphorylation and endocytosis (168). Cav-1 phosphorylation at Tyr (14) following LPS exposure promotes Cav-1 and TLR4 interaction leading to NF-κB activation and generation of proinflammatory cytokines (77,88).…”

Section: Translational Regulationmentioning

confidence: 99%

Myocardial Tissue Caveolae

Sanon

Sawaki

Mjaatvedt

et al. 2015

Comprehensive Physiology

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Caveolae and their coat proteins, caveolins (Cav), are cave-like invaginations found in the plasma membrane of a variety of cells. These unique vesicles and their coat proteins, Cavs, have diverse effects on endothelial function, nitric oxide synthesis regulation, signal transduction, cholesterol metabolism, and apoptosis. Animal studies in Cav knockout mice demonstrate the vital role of these structural proteins on endothelial and vascular function. Genetic studies have proposed that beside neoplasia, Cavs may play a role in the development of atherosclerosis, cardiomyopathy, long QT syndrome, pulmonary fibrosis, and muscular dystrophy. The role of Cav expression in atherosclerotic disease is poorly understood and remains controversial. Interestingly, there is emerging evidence between low Cav-1 levels and the vulnerable plaque, which could potentially identify Cav-1 as a novel plaque biomarker. Cavs, through intricate biochemical pathways involving endothelial nitric oxide synthase and mitogen-activated protein kinase, are known to affect the cardiovascular system at multiple levels. In the present review, we aim to highlight the nature and types of caveolae, caveolar signaling mechanisms and regulation, and the pathophysiology of Cavs as it pertains to the cardiovascular system. Ongoing research is needed to clarify the diagnostic and prognostic role of these novel proteins and to determine how the effects of Cavs can translate into clinical medicine.

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AMP-dependent Kinase Inhibits Oxidative Stress-induced Caveolin-1 Phosphorylation and Endocytosis by Suppressing the Dissociation between c-Abl and Prdx1 Proteins in Endothelial Cells

Cited by 38 publications

References 54 publications

Effects of selenoprotein S on oxidative injury in human endothelial cells

Effects of selenoprotein S on oxidative injury in human endothelial cells

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

Myocardial Tissue Caveolae

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