title: Mitochondria-derived reactive oxygen species and vascular MAP kinases: comparison of angiotensin II and diazoxide.
abstract: Reactive oxygen species (ROS) are key mediators in signal transduction of angiotensin II (Ang II). However, roles of vascular mitochondria, a major intracellular ROS source, in response to Ang II stimuli have not been elucidated. This study aimed to examine the involvement of mitochondria-derived ROS in the signaling pathway and the vasoconstrictor mechanism of Ang II. Using 5-hydroxydecanoate (5-HD; a specific inhibitor of mitochondrial ATP-sensitive potassium [mitoK(ATP)] channels) and tempol (a superoxide dismutase mimetic), the effects of Ang II and diazoxide (a mitoK(ATP) channel opener) were compared on redox-sensitive mitogen-activated protein (MAP) kinase activation in rat vascular smooth muscle cells (RVSMCs) in vitro and in rat aorta in vivo. Stimulation of RVSMCs by Ang II or diazoxide increased phosphorylated MAP kinases (ERK1/2, p38, and JNK), as well as superoxide production, which were then suppressed by 5-HD pretreatment in a dose-dependent manner, except for ERK1/2 activation by Ang II. The same events were reproduced in rat aorta in vivo. Ang II-like diazoxide depolarized the mitochondrial membrane potential (DeltaPsi(M)) of RVSMCs determined by JC-1 fluorescence, which was inhibited by 5-HD. 5-HD did not modulate Ang II-induced calcium mobilization in RVSMCs and did not affect on the vasoconstrictor effect in either acute or chronic phases of Ang II-induced hypertension. These results reveal that Ang II stimulates mitochondrial ROS production through the opening of mitoK(ATP) channels in the vasculature-like diazoxide, leading to reduction of DeltaPsi(M) and redox-sensitive activation of MAP kinase; however, generated ROS from mitochondria do not contribute to Ang II-induced vasoconstriction.
authors.affiliation: Department of Pharmacology, Kagawa University Medical School, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan. kimura@kms.ac.jp
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Guo-Xing
authors.initials: GX
authors.lastname: Zhang
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Takatomi
authors.initials: T
authors.lastname: Shokoji
authors.forename: Li
authors.initials: L
authors.lastname: Yao
authors.forename: Yu-Yan
authors.initials: YY
authors.lastname: Fan
authors.forename: Matlubur
authors.initials: M
authors.lastname: Rahman
authors.forename: Youichi
authors.initials: Y
authors.lastname: Abe
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000166:cytology / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D007425:Intracellular Membranes / Q000378:metabolism / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013113:Spin Labels; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D003652:Decanoic Acids; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D013113:Spin Labels; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; C052853:5-hydroxydecanoic acid; D020928:Mitogen-Activated Protein Kinases; D003981:Diazoxide; D002118:Calcium; C001803:tempol