PMID- 24397980 OWN - NLM STAT- MEDLINE DCOM- 20140428 LR - 20211021 IS - 1524-4571 (Electronic) IS - 0009-7330 (Print) IS - 0009-7330 (Linking) VI - 114 IP - 5 DP - 2014 Feb 28 TI - Adiponectin inhibits tumor necrosis factor-alpha-induced vascular inflammatory response via caveolin-mediated ceramidase recruitment and activation. PG - 792-805 LID - 10.1161/CIRCRESAHA.114.302439 [doi] AB - 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)alpha-induced intercellular adhesion molecule-1 expression and attenuated TNFalpha-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 TNFalpha-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 TNFalpha-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 TNFalpha-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion. FAU - Wang, Yajing AU - Wang Y AD - From the Department of Emergency Medicine (Y.W., X.W., W.B.L., Y.Y., J.-J.L., X.-L.M.) and Department of Pathology (D.B.), Thomas Jefferson University, Philadelphia, PA; and Department of Physiology, Cardiovascular Research Center (R.S., K.P.) and Center for Translational Medicine (E.G., W.K.), Temple University, Philadelphia, PA. FAU - Wang, Xiaoliang AU - Wang X FAU - Lau, Wayne Bond AU - Lau WB FAU - Yuan, Yuexing AU - Yuan Y FAU - Booth, David AU - Booth D FAU - Li, Jing-Jing AU - Li JJ FAU - Scalia, Rosario AU - Scalia R FAU - Preston, Kyle AU - Preston K FAU - Gao, Erhe AU - Gao E FAU - Koch, Walter AU - Koch W FAU - Ma, Xin-Liang AU - Ma XL LA - eng GR - S10 OD010408/OD/NIH HHS/United States GR - HL-096686/HL/NHLBI NIH HHS/United States GR - R01 HL096686/HL/NHLBI NIH HHS/United States GR - HL-63828/HL/NHLBI NIH HHS/United States GR - R01 HL063828/HL/NHLBI NIH HHS/United States GR - T32 HL091804/HL/NHLBI NIH HHS/United States GR - R01 DK096521/DK/NIDDK NIH HHS/United States GR - 5R01DK064344/DK/NIDDK NIH HHS/United States GR - P01 HL108806/HL/NHLBI NIH HHS/United States GR - R01 DK064344/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140107 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (ADIPOQ protein, human) RN - 0 (ADIPOR1 protein, human) RN - 0 (ADIPOR2 protein, human) RN - 0 (Adiponectin) RN - 0 (CAV1 protein, human) RN - 0 (Caveolin 1) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Nitrogen Species) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, Adiponectin) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.5.1.23 (Ceramidases) SB - IM MH - Adiponectin/immunology/*metabolism MH - Caveolin 1/genetics/immunology/*metabolism MH - Ceramidases/genetics/immunology/*metabolism MH - Endothelial Cells/immunology MH - Enzyme Activation/immunology MH - Gene Knockdown Techniques MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Leukocyte Rolling/immunology MH - RNA, Small Interfering/genetics MH - Reactive Nitrogen Species/immunology/metabolism MH - Reactive Oxygen Species/immunology/metabolism MH - Receptors, Adiponectin/genetics/immunology/metabolism MH - Signal Transduction/immunology MH - Tumor Necrosis Factor-alpha/immunology/*metabolism MH - Vasculitis/immunology/*metabolism PMC - PMC3961763 MID - NIHMS559942 OTO - NOTNLM OT - adipokines OT - endothelial cells OT - inflammation OT - sphingolipids OT - vascular system injuries EDAT- 2014/01/09 06:00 MHDA- 2014/04/29 06:00 PMCR- 2015/02/28 CRDT- 2014/01/09 06:00 PHST- 2014/01/09 06:00 [entrez] PHST- 2014/01/09 06:00 [pubmed] PHST- 2014/04/29 06:00 [medline] PHST- 2015/02/28 00:00 [pmc-release] AID - CIRCRESAHA.114.302439 [pii] AID - 10.1161/CIRCRESAHA.114.302439 [doi] PST - ppublish SO - Circ Res. 2014 Feb 28;114(5):792-805. doi: 10.1161/CIRCRESAHA.114.302439. Epub 2014 Jan 7.