Adiponectin protects against angiotensin II or tumor necrosis factor alpha-induced endothelial cell monolayer hyperpermeability: role of cAMP/PKA signaling.
OBJECTIVE
Angiotensin II (Ang II) and tumor necrosis factor (TNF)-alpha levels increase endothelial permeability, and we hypothesized that adiponectin suppressed these responses in a cAMP-dependent manner.


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-alpha (5 ng/mL) was measured. Treatment with the globular domain of adiponectin (3 mug/mL) for 16 hours abrogated the adverse TEER effect of TNF-alpha (-35 versus -12 Omega/cm(2) at 45 minutes, P<0.05) and Ang II (-25 versus -5 Omega/cm(2) 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-alpha (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 beta-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-alpha-induced hyperpermeability by modulating microtubule and cytoskeleton stability via a cAMP/ PKA signaling cascade.
Xu
Shi-Qiong
SQ
Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pa. 19107, USA.
Mahadev
Kalyankar
K
Wu
Xiangdong
X
Fuchsel
Lauren
L
Donnelly
Sylvia
S
Scalia
Rosario G
RG
Goldstein
Barry J
BJ
D000199:Actins / Q000378:metabolism; D052242:Adiponectin / Q000502:physiology*; D000418:Albumins / Q000378:metabolism; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D002417:Cattle; D002463:Cell Membrane Permeability / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000199:Actins; D052242:Adiponectin; D000418:Albumins; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases