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Adiponectin Suppression of High-Glucose–Induced Reactive Oxygen Species in Vascular Endothelial Cells

Evidence for Involvement of a cAMP Signaling Pathway

¹ Dorrance Hamilton Research Laboratories, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania
² Department of Physiology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania

Address correspondence and reprint requests to Barry J. Goldstein, MD, PhD, Director, Division of Endocrinology, DiabetesMetabolic Diseases, Department of Medicine, Jefferson Medical College, Suite 349, 1020 Locust St., Philadelphia, PA 19107. E-mail: barry.goldstein{at}jefferson.edu

Abbreviations: AICAR, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside; AMPK, 5'-AMP–activated protein kinase; ara-A, adenine-9-ß-D-arabinofuranoside; BAEC, bovine aortic endothelial cell; fAd, full-length adiponectin protein; gAd, globular domain of human adiponectin; HUVEC, human umbilical vein endothelial cell; PKA, cAMP-dependent protein kinase; ROS, reactive oxygen species; TNF-, tumor necrosis factor-

Adiponectin is an abundant adipocyte-derived plasma protein with antiatherosclerotic effects. Vascular signal transduction by adiponectin is poorly understood and may involve 5'-AMP–activated protein kinase (AMPK), cAMP signaling, and other pathways. Hyperglycemia sharply increases the production of reactive oxygen species (ROS), which play a key role in endothelial dysfunction in diabetes. Because the recombinant globular domain of human adiponectin (gAd) reduces the generation of endothelial ROS induced by oxidized LDL, we sought to determine whether adiponectin could also suppress ROS production induced by high glucose in cultured human umbilical vein endothelial cells. Incubation in 25 mmol/l glucose for 16 h increased ROS production 3.8-fold (P < 0.05), using a luminol assay. Treatment with gAd for 16 h suppressed glucose-induced ROS in a dose-dependent manner up to 81% at 300 nmol/l (P < 0.05). The AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR; 1 mmol/l, 16 h) only partially decreased glucose-induced ROS by 22% (P < 0.05). Cell pretreatment with AMPK inhibitors, however, failed to block the effect of gAd to suppress glucose-induced ROS, suggesting that the action of gAd was independent of AMPK. Interestingly, activation of cAMP signaling by treatment with forskolin (2 µmol/l) or dibutyryl-cAMP (0.5 mmol/l) reduced glucose-induced ROS generation by 43 and 67%, respectively (both P < 0.05). Incubation with the cAMP-dependent protein kinase (PKA) inhibitor H-89 (1 µmol/l) fully abrogated the effect of gAd, but not that of AICAR, on ROS induced by glucose. gAd also increased cellular cAMP content by 70% in an AMPK-independent manner. Full-length adiponectin purified from a eukaryotic expression system also suppressed ROS induced by high glucose or by treatment of endothelial cells with oxidized LDL. Thus, adiponectin suppresses excess ROS production under high-glucose conditions via a cAMP/PKA-dependent pathway, an effect that has implications for vascular protection in diabetes.

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