Adiponectin Protects Against Angiotensin II or Tumor Necrosis Factor Induced Endothelial Cell Monolayer Hyperpermeability

Role of cAMP/PKA Signaling

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Shi-Qiong Xu, Kalyankar Mahadev, Xiangdong Wu, Lauren Fuchsel, Sylvia Donnelly, Rosario G. Scalia, Barry J. Goldstein

+ Author Affiliations 1. From the Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine (S.-Q.X., K.M., X.W., L.F., S.D., B.J.G.), and the Department of Molecular Physiology and Biophysics (R.G.S.), Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pa. 1. Correspondence to Barry J. Goldstein, MD, PhD, Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Room 320 Curtis Building, 1015 Walnut Street, Philadelphia, PA 19107. E-mail Barry.Goldstein@jefferson.edu

Abstract
Objective Angiotensin II (Ang II) and tumor necrosis factor (TNF)- 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- (5 ng/mL) was measured. Treatment with the globular domain of adiponectin (3 g/mL) for 16 hours abrogated the adverse TEER effect of TNF- (35 versus 12 /cm2 at 45 minutes, P<0.05) and Ang II (25 versus 5 /cm2 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- (40% versus 20% change, P<0.05). Full-length adiponectin also suppressed Ang II induced monolayer hyperpermeability. Adiponectin treatment also suppressed Ang IIinduced increased actin stress fiber development, intercellular gap formation, and -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--induced hyperpermeability by modulating microtubule and cytoskeleton stability via a cAMP/ PKA signaling cascade.