School of Medical Sciences
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Browsing School of Medical Sciences by Subject "Adiponectin"
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ItemAdiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells( 2008-05-01) Mahadev, Kalyankar ; Wu, Xiangdong ; Donnelly, Sylvia ; Ouedraogo, Raogo ; Eckhart, Andrea D. ; Goldstein, Barry J.Aims: Vascular endothelial growth factor (VEGF)-induced endothelial cell migration and angiogenesis are associated with the vascular complications of diabetes mellitus, and adiponectin is an abundant plasma adipokine that exhibits salutary effects on endothelial function. We investigated whether adiponectin suppresses VEGF-induced migration and related signal transduction responses in human coronary artery endothelial cells (HCAECs). Methods and results: Using a modified Boyden chamber technique and a monolayer 'wound-healing' assay, both the recombinant adiponectin globular domain and full-length adiponectin protein potently suppressed the migration of HCAEC induced by VEGF. Adiponectin did not increase endothelial cell apoptosis, as measured by Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labelling assay. Adiponectin also suppressed VEGF-induced reactive oxygen species generation, activation of Akt, the mitogen-activated protein kinase ERK and the RhoGTPase RhoA, and induction of the formation of actin stress fibres and focal cellular adhesions. VEGF-stimulated cell migration was inhibited by activation of adenylyl cyclase with forskolin, and adiponectin treatment increased cellular cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) enzymatic activity. Pharmacological inhibition of either adenylyl cyclase or PKA significantly abrogated the effect of adiponectin globular domain to suppress VEGF-induced cell migration. Conclusion: Adiponectin suppresses VEGF-stimulated HCAEC migration via cAMP/PKA-dependent signalling, an important effect with implications for a regulatory role of adiponectin in vascular processes associated with diabetes and atherosclerosis. © The Author 2008.
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ItemAdiponectin protects against angiotensin II or tumor necrosis factor α-induced endothelial cell monolayer hyperpermeability: Role of cAMP/PKA signaling( 2008-05-01) Xu, Shi Qiong ; Mahadev, Kalyankar ; Wu, Xiangdong ; Fuchsel, Lauren ; Donnelly, Sylvia ; Scalia, Rosario G. ; Goldstein, Barry J.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.