Roles of Phosphatidylinositol 3-Kinase-Akt and NADPH Oxidase in Adenosine 5' -Triphosphate-Sensitive K+ Channel Function Impaired by High Glucose in the Human Artery

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2008-09, Vol.52 (3), p.507-513
• Main Authors: KINOSHITA, Hiroyuki, MATSUDA, Naoyuki, KABA, Hikari, HATAKEYAMA, Noboru, AZMA, Toshiharu, NAKAHATA, Katsutoshi, KURODA, Yasuhiro, TANGE, Kazuaki, IRANAMI, Hiroshi, HATANO, Yoshio
• Format: Article
• Language: English
• Subjects: Antihypertensive Agents - pharmacology; Arterial hypertension. Arterial hypotension; Arteries - cytology; Arteries - drug effects; Arteries - enzymology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Chromones - pharmacology; Cromakalim - pharmacology; Enzyme Inhibitors - pharmacology; Experimental diseases; Glucose - pharmacology; Glyburide - pharmacology; Humans; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hypoglycemic Agents - pharmacology; In Vitro Techniques; KATP Channels - metabolism; Medical sciences; Morpholines - pharmacology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; NADPH Oxidases - metabolism; Omentum - blood supply; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; rac1 GTP-Binding Protein - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Superoxides - metabolism
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.108.118216

The present study was designed to examine roles of the phosphatidylinositol 3-kinase-Akt pathway and reduced nicotinamide-adenine dinucleotide phosphate oxidases in the reduced ATP-sensitive K(+) channel function via superoxide produced by high glucose in the human artery. We evaluated the activity of the phosphatidylinositol 3-kinase-Akt pathway, as well as reduced nicotinamide-adenine dinucleotide phosphate oxidases, the intracellular levels of superoxide and ATP-sensitive K(+) channel function in the human omental artery without endothelium. Levels of the p85-alpha subunit and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits, including p47phox, p22phox, and Rac-1, increased in the membrane fraction from arteries treated with D-glucose (20 mmol/L) accompanied by increased intracellular superoxide production. High glucose simultaneously augmented Akt phosphorylation at Ser 473, as well as Thr 308 in the human vascular smooth muscle cells. A phosphatidylinositol 3-kinase inhibitor LY294002, as well as tiron and apocynin, restored vasorelaxation and hyperpolarization in response to an ATP-sensitive K(+) channel opener levcromakalim. Therefore, it can be concluded that the activation of the phosphatidylinositol 3-kinase-Akt pathway, in combination with the translocation of p47phox, p22phox, and Rac-1, contributes to the superoxide production induced by high glucose, resulting in the impairment of ATP-sensitive K(+) channel function in the human visceral artery.