Adiponectin Inhibits Tumor Necrosis Factor-α–Induced Vascular Inflammatory Response via Caveolin-Mediated Ceramidase Recruitment and Activation

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)α–induced intercellular adhesion molecule-1 expression and attenuated TNFα-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-mediat...