Adiponectin protects against angiotensin II or tumor necrosis factor α-induced endothelial cell monolayer hyperpermeability: Role of cAMP/PKA signaling

Abstract

OBJECTIVE - Angiotensin II (Ang II) and tumor necrosis factor (TNF)-α levels increase endothelial permeability, and we hypothesized that adiponectin suppressed these responses in a cAMP-dependent manner. METHODS AND RESULTS - The effect of adiponectin on transendothelial electric resistance (TEER) and diffusion of albumin through human umbilical vein and bovine aortic endothelial cell monolayers induced by Ang II (100 nmol/L) or TNF-α (5 ng/mL) was measured. Treatment with the globular domain of adiponectin (3 μg/mL) for 16 hours abrogated the adverse TEER effect of TNF-α (-35 versus -12 Ω/cm at 45 minutes, P < 0.05) and Ang II (-25 versus -5 Ω/cm at 45 minutes, P < 0.01) and partially suppressed the increased diffusion of albumin with Ang II (40% versus 10% change, P < 0.05) or TNF-α (40% versus 20% change, P < 0.05). Full-length adiponectin also suppressed Ang II-induced monolayer hyperpermeability. Adiponectin treatment also suppressed Ang II-induced increased actin stress fiber development, intercellular gap formation, and β-tubulin disassembly. Adiponectin increased cAMP levels, and its effects were abrogated by inhibition of adenylyl cyclase or cAMP-dependent protein kinase signaling. CONCLUSIONS - Adiponectin protects the endothelial monolayer from Ang II or TNF-α-induced hyperpermeability by modulating microtubule and cytoskeleton stability via a cAMP/ PKA signaling cascade. © 2008 American Heart Association, Inc.