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.
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.
Kinoshita
Hiroyuki
H
Department of Anesthesiology, Wakayama Medical University, Wakayama, Japan. hkinoshi@pd5.so-net.ne.jp
Matsuda
Naoyuki
N
Kaba
Hikari
H
Hatakeyama
Noboru
N
Azma
Toshiharu
T
Nakahata
Katsutoshi
K
Kuroda
Yasuhiro
Y
Tange
Kazuaki
K
Iranami
Hiroshi
H
Hatano
Yoshio
Y
D000959:Antihypertensive Agents / Q000494:pharmacology; D001158:Arteries / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002867:Chromones / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism*; D009852:Omentum / Q000098:blood supply; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000959:Antihypertensive Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D054086:KATP Channels; D009025:Morpholines; C107953:RAC1 protein, human; D019806:Cromakalim; D013481:Superoxides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; D005947:Glucose; D005905:Glyburide