Adiponectin Inhibits TNF-α-Induced Vascular Inflammatory Response via Caveolin-Mediated Ceramidase Recruitment and Activation

Rationale: Anti-inflammatory and vascular protective actions of adiponectin (APN) are well-recognized. However, many fundamental questions remain unanswered. Objective: The current study attempted to identify the APN receptor subtype responsible for APN9s vascular protective action, and investigate the role of ceramidase activation in APN anti-inflammatory signaling. Methods and Results: APN significantly reduced TNFα-induced ICAM-1 expression and attenuated TNFα-induced oxidative/nitrative stress in HUVECs. These anti-inflammatory actions were virtually abolished by AdipoR1-, but not AdipoR2-, knockdown (KD). Treatment with APN significantly increased neutral ceramidase (nCDase) activity (3.7-fold, P 87% of APN-induced nCDase activation was lost. Whereas APN treatment failed to inhibit TNFα-induced ICAM-1 expression, treatment with S1P or SEW (S1P receptor agonist) remained effective in Cav1-KD cells. AdipoR1 and Cav1 co-localized and co-precipitated in HUVECs. APN treatment did not affect this interaction. There is weak basal Cav1/nCDase interaction, which significantly increased following APN treatment. Knockout of AdipoR1 or Cav1 abolished the inhibitory effect of APN upon leukocyte rolling and adhesion in vivo. Conclusions: These results demonstrate for the first time that APN inhibits TNFα-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion.