Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway

Zhang, Ying; Zhan, Ri-Xin; Chen, Jun-Qun; Gao, Yan; Chen, Li; Kong, Ying; Zhong, Xiao-Juan; Liu, Meiqi; Chu, Jia-Jia; Yan, Guoqiang; Li, Teng; He, Ming; Huang, Qiren

doi:10.1016/j.ejphar.2015.02.004

Cited by 28 publications

(22 citation statements)

References 41 publications

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“…PPAR-γ activation is able to alleviate inflammation response in endothelial cells [37]. Pharmacological activation of PPAR-γ ameliorates the levels of TNF-α, IL-6, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cellular adhesion molecule-1 (sVCAM-1) in endothelial cells [38]. In this study, we exhibited that LPS dose-dependently inhibited both protein and mRNA levels of PPAR-γ, and Hy obviously attenuated LPS-induced suppression of PPAR-γ expression.…”

Section: Discussionmentioning

confidence: 99%

Hypaphorine Attenuates Lipopolysaccharide-Induced Endothelial Inflammation via Regulation of TLR4 and PPAR-γ Dependent on PI3K/Akt/mTOR Signal Pathway

Sun

Zhu

Cai

et al. 2017

IJMS

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Endothelial lesion response to injurious stimuli is a necessary step for initiating inflammatory cascades in blood vessels. Hypaphorine (Hy) from different marine sources is shown to exhibit anti-inflammatory properties. However, the potential roles and possible molecular mechanisms of Hy in endothelial inflammation have yet to be fully clarified. We showed that Hy significantly inhibited the positive effects of lipopolysaccharide (LPS) on pro-inflammatory cytokines expressions, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein 1 (MCP-1) and vascular cellular adhesion molecule-1 (VCAM-1), as well as induction of the phosphorylation of Akt and mTOR in HMEC-1 cells. The downregulated peroxisome proliferator-activated receptor γ (PPAR-γ) and upregulated toll-like receptor 4 (TLR4) expressions in LPS-challenged endothelial cells were prevented by Hy. Inhibition of both PI3K and mTOR reversed LPS-stimulated increases in TLR4 expressions and decreases in PPAR-γ levels. Genetic silencing of TLR4 or PPAR-γ agonist pioglitazone obviously abrogated the levels of pro-inflammatory cytokines in LPS-treated HMEC-1 cells. These results suggest that Hy may exert anti-inflammatory actions through the regulation of TLR4 and PPAR-γ dependent on PI3K/Akt/mTOR signal pathways. Hy may be considered as a therapeutic agent that can potentially relieve or ameliorate endothelial inflammation-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Hypaphorine Attenuates Lipopolysaccharide-Induced Endothelial Inflammation via Regulation of TLR4 and PPAR-γ Dependent on PI3K/Akt/mTOR Signal Pathway

Sun

Zhu

Cai

et al. 2017

IJMS

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“…Peroxisome proliferator-activated receptor gamma (PPARg) is the target of clinical insulin sensitizers, which can protect diabetes and related complication, such as endothelial cell injury and vascular endothelial insulin resistance (IR) induced by high glycemic (Zhang et al, 2015). Research on the variance in gene expression profiles in the renal cortex of diabetic nephropathy rats treated with Rg3 showed that the PPAR signaling pathway was predominantly altered, indicating that PPAR is involved in mechanisms underlying Rg3 improving diabetic nephropathy (Wang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rg3 Alleviates ox-LDL Induced Endothelial Dysfunction and Prevents Atherosclerosis in ApoE−/− Mice by Regulating PPARγ/FAK Signaling Pathway

Geng

et al. 2020

Front. Pharmacol.

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The initiation of atherosclerosis (AS) induced by dyslipidemia is accompanied by endothelial dysfunction, including decreased healing ability and increased recruitment of monocytes. Studies showed ginsenoside Rg3 has potential to treat diseases associated with endothelial dysfunction which can protects against antineoplastic drugs induced cardiotoxicity by repairing endothelial function, while the effect and mechanism of Rg3 on dyslipidemia induced endothelial dysfunction and AS are not clear. Therefore, we investigated the effects of Rg3 on oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) dysfunction and high-fat diets (HFD) induced atherosclerosis in ApoE −/− mice, as well as the mechanism. For in vitro assay, Rg3 enhanced healing of HUVECs and inhibited human monocytes (THP-1) adhesion to HUVECs disturbed by ox-LDL, down-regulated focal adhesion kinase (FAK)-mediated expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1); restrained the FAK-mediated non-adherent dependent pathway containing matrix metalloproteinase (MMP)-2/9 expression, activation of nuclear factorkappa B (NF-kB), high mRNA levels of monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6), besides Rg3 up-regulated peroxisome proliferators-activated receptor g (PPARg) in ox-LDL-stimulated HUVECs. GW9662, the PPARg-specific inhibitor, can repressed the effects of Rg3 on ox-LDL-stimulated HUVECs. For in vivo assay, Rg3 significantly reduced atherosclerotic pathological changes in ApoE −/− mice fed with HFD, up-regulated PPARg, and inhibited activation FAK in aorta, thus inhibited expression of VCAM-1, ICAM-1 in intima. We conclude that Rg3 may protect endothelial cells and inhibit atherosclerosis by up-regulating PPARg via repressing FAK-mediated pathways, indicating that Rg3 have good potential in preventing dyslipidemia induced atherosclerosis.

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“…The methods for establishment of endothelium IR model in vitro and in vivo have previously been described in details . Briefly, HUVEC with a 90% confluence was first pre‐treated with a complete DMEM containing 33 m mol L −1 of glucose (HG) for 48 hours.…”

Section: Methodsmentioning

confidence: 99%

“…Also, fasting plasma glucose (FPG) and serum insulin (FINS), triglyceride(TG), cholesterol (CH) as well as the homoeostatic model assay of IR (HOMA‐IR) were tested. In addition, the serum levels of nitrite and ET‐1 as well as the expression of AKT and p‐AKT from aorta tissue were assayed before modelling (pre‐model) and after modelling (post‐model) …”

Section: Methodsmentioning

confidence: 99%

“…Although TZDs have anti‐diabetic and anti‐atherogenic effects by acting on macrophages and lymphocytes by trans‐repressing nuclear factor kappaB‐ (NFκB‐) dependent target genes, the effects of TZDs on vascular endothelial cells and the underlying mechanisms remain poorly understood. Our recent data revealed that TZDs improved vascular endothelium IR induced by high concentration of glucose /hyperglycaemia (HG) through a PPARγ‐dependent NFκB trans‐repression mechanism . However, it is unclear whether changes in PPARγ expression affect endothelium IR and what the underlying mechanism is.…”

Section: Introductionmentioning

confidence: 99%

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Trans‐repression ofNFκB pathway mediated byPPARγ improves vascular endothelium insulin resistance

Kong

Gao

Lan

et al. 2018

J Cellular Molecular Medi

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Previous study has shown that thiazolidinediones (TZDs) improved endothelium insulin resistance (IR) induced by high glucose concentration (HG)/hyperglycaemia through a PPARγ‐dependent‐NFκB trans‐repression mechanism. However, it is unclear, whether changes in PPARγ expression affect the endothelium IR and what the underlying mechanism is. In the present study, we aimed to address this issue. HG‐treated human umbilical vascular endothelial cells (HUVEC) were transfected by either PPARγ‐overexpressing (Ad‐PPARγ) or PPARγ‐shRNA‐containing (Ad‐PPARγ‐shRNA) adenoviral vectors. Likewise, the rats fed by high‐fat diet (HFD) were infected by intravenous administration of Ad‐PPARγ or Ad‐PPARγ‐shRNA. The levels of nitric oxide (NO), endothelin‐1 (ET‐1) and cytokines (TNFα, IL‐6, sICAM‐1 and sVCAM‐1) and the expression levels of PPARγ, eNOS, AKT, p‐AKT, IKKα/β and p‐IKKα/β and IκBα were examined; and the interaction between PPARγ and NFκB‐P65 as well as vascular function were evaluated. Our present results showed that overexpression of PPARγ notably increased the levels of NO, eNOS, p‐AKT and IκBα as well as the interaction of PPARγ and NFκB‐P65, and decreased the levels of ET‐1, p‐IKKα/β, TNFα, IL‐6, sICAM‐1 and sVCAM‐1. In contrast, down‐expression of PPARγ displayed the opposite effects. The results demonstrate that the overexpression of PPARγ improves while the down‐expression worsens the endothelium IR via a PPARγ‐mediated NFκB trans‐repression dependent manner. The findings suggest PPARγ is a potential therapeutic target for diabetic vascular complications.

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Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway

Cited by 28 publications

References 41 publications

Hypaphorine Attenuates Lipopolysaccharide-Induced Endothelial Inflammation via Regulation of TLR4 and PPAR-γ Dependent on PI3K/Akt/mTOR Signal Pathway

Hypaphorine Attenuates Lipopolysaccharide-Induced Endothelial Inflammation via Regulation of TLR4 and PPAR-γ Dependent on PI3K/Akt/mTOR Signal Pathway

Ginsenoside Rg3 Alleviates ox-LDL Induced Endothelial Dysfunction and Prevents Atherosclerosis in ApoE−/− Mice by Regulating PPARγ/FAK Signaling Pathway

Trans‐repression ofNFκB pathway mediated byPPARγ improves vascular endothelium insulin resistance

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