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Adiponectin inhibits tumor necrosis factor-?-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation.

ABSTRACT: RATIONALE:Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered. OBJECTIVE:The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin's vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling. METHODS AND RESULTS:Adiponectin significantly reduced tumor necrosis factor (TNF)?-induced intercellular adhesion molecule-1 expression and attenuated TNF?-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P<0.01). AdipoR1-KD markedly reduced globular adiponectin-induced nCDase activation, whereas AdipoR2-KD only slightly reduced. More importantly, small interfering RNA-mediated nCDase-KD markedly blocked the effect of adiponectin on TNF?-induced intercellular adhesion molecule-1 expression. AMP-activated protein kinase-KD failed to block adiponectin-induced nCDase activation and modestly inhibited adiponectin anti-inflammatory effect. In contrast, in caveolin-1 KD (Cav1-KD) cells, >87% of adiponectin-induced nCDase activation was lost. Whereas adiponectin treatment failed to inhibit TNF?-induced intercellular adhesion molecule-1 expression, treatment with sphingosine-1-phosphate or SEW (sphingosine-1-phosphate receptor agonist) remained effective in Cav1-KD cells. AdipoR1 and Cav1 colocalized and coprecipitated in human umbilical vein endothelial cells. Adiponectin treatment did not affect this interaction. There is weak basal Cav1/nCDase interaction, which significantly increased after adiponectin treatment. Knockout of AdipoR1 or Cav1 abolished the inhibitory effect of adiponectin on leukocyte rolling and adhesion in vivo. CONCLUSIONS:These results demonstrate for the first time that adiponectin inhibits TNF?-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3961763 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Adiponectin inhibits tumor necrosis factor-α-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation.

Wang Yajing Y Wang Xiaoliang X Lau Wayne Bond WB Yuan Yuexing Y Booth David D Li Jing-Jing JJ Scalia Rosario R Preston Kyle K Gao Erhe E Koch Walter W Ma Xin-Liang XL

Circulation research 20140107 5

<h4>Rationale</h4>Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered.<h4>Objective</h4>The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin's vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling.<h4>Methods and results</h4>Adiponectin significantly reduced tumor necrosis factor (TNF)α-induced in ...[more]

PMID: 24397980

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Project description:ObjectivesIn this study, we explored how adiponectin mediated urotensin II (UII)‍-induced tumor necrosis factor-‍α (TNF-‍α) and α‍-smooth muscle actin (α‍-SMA) expression and ensuing intracellular signaling pathways in adventitial fibroblasts (AFs).MethodsGrowth-arrested AFs and rat tunica adventitia of vessels were incubated with UII and inhibitors of signal transduction pathways for 1‍‒‍24 h. The cells were then harvested for TNF-α receptor (TNF-‍α-R) messenger RNA (mRNA) and TNF-‍α protein expression determination by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Adiponectin and adiponectin receptor (adipoR) expression was measured by RT-PCR, quantitative real-time PCR (qPCR), immunohistochemical analysis, and cell counting kit-8 (CCK-8) cell proliferation experiments. We then quantified TNF-α and α-SMA mRNA and protein expression levels by qPCR and immunofluorescence (IF) staining. RNA interference (RNAi) was used to explore the function of the adipoR genes. To investigate the signaling pathway, we applied western blotting (WB) to examine phosphorylation of adenosine 5'-monophosphate (AMP)‍-activated protein kinase (AMPK). In vivo, an adiponectin (APN)‍-knockout (APN-KO) mouse model mimicking adventitial inflammation was generated to measure TNF-α and α‍-SMA expression by application of qPCR and IF, with the goal of gaining a comprehensive atlas of adiponectin in vascular remodeling.ResultsIn both cells and tissues, UII promoted TNF-α protein and TNF-α-R secretion in a dose- and time-dependent manner via Rho/protein kinase C (PKC) pathway. We detected marked expression of adipoR1, T-cadherin, and calreticulin as well as a moderate presence of adipoR2 in AFs, while no adiponectin was observed. Globular adiponectin (gAd) fostered the growth of AFs, and acted in concert with UII to induce α-SMA and TNF-α through the adipoR1/T-cadherin/calreticulin/AMPK pathway. In AFs, gAd and UII synergistically induced AMPK phosphorylation. In the adventitial inflammation model, APN deficiency up-regulated the expression of α-SMA, UII receptor (UT), and UII while inhibiting TNF-‍α expression.ConclusionsFrom the results of our study, we can speculate that UII induces TNF‍-‍α protein and TNF-‍α‍-R secretion in AFs and rat tunica adventitia of vessels via the Rho and PKC signal transduction pathways. Thus, it is plausible that adiponectin is a major player in adventitial progression and could serve as a novel therapeutic target for cardiovascular disease administration.

Dataset Information

Adiponectin inhibits tumor necrosis factor-?-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation.

Publications

Adiponectin inhibits tumor necrosis factor-α-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation.

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