title: Obligatory role of intraluminal O2- in acute endothelin-1 and angiotensin II signaling to mediate endothelial dysfunction and MAPK activation in guinea-pig hearts.
abstract: We hypothesized that, due to a cross-talk between cytoplasmic O2--sources and intraluminally expressed xanthine oxidase (XO), intraluminal O2- is instrumental in mediating intraluminal (endothelial dysfunction) and cytosolic (p38 and ERK1/2 MAPKs phosphorylation) manifestations of vascular oxidative stress induced by endothelin-1 (ET-1) and angiotensin II (AT-II). Isolated guinea-pig hearts were subjected to 10-min agonist perfusion causing a burst of an intraluminal O2-. ET-1 antagonist, tezosentan, attenuated AT-II-mediated O2-, indicating its partial ET-1 mediation. ET-1 and Ang-T (AT-II+tezosentan) triggered intraluminal O2-, endothelial dysfunction, MAPKs and p47phox phosphorylation, and NADPH oxidase (Nox) and XO activation. These effects were: (i) prevented by blocking PKC (chelerythrine), Nox (apocynin), mitochondrial ATP-dependent K+ channel (5-HD), complex II (TTFA), and XO (allopurinol); (ii) mimicked by the activation of Nox (NADH); and mitochondria (diazoxide, 3-NPA) and (iii) the effects by NADH were prevented by 5-HD, TTFA and chelerythrine, and those by diazoxide and 3-NPA by apocynin and chelerythrine, suggesting that the agonists coactivate Nox and mitochondria, which further amplify their activity via PKC. The effects by ET-1, Ang-T, NADH, diazoxide, and 3-NPA were opposed by blocking intraluminal O2- (SOD) and XO, and were mimicked by XO activation (hypoxanthine). Apocynin, TTFA, chelerythrine, and SOD opposed the effects by hypoxanthine. In conclusion, oxidative stress by agonists involves cellular inside-out and outside-in signaling in which Nox-mitochondria-PKC system and XO mutually maintain their activities via the intraluminal O2-.
authors.affiliation: Department of Clinical Physiology, Postgraduate Medical School, Warsaw 01-813, Poland. emiliak567@gmail.com.
authors.forename: Emilia
authors.initials: E
authors.lastname: Wojtera
authors.affiliation: Department of Clinical Physiology, Postgraduate Medical School, Warsaw 01-813, Poland. niakon@wp.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Konior
authors.affiliation: Department of Clinical Physiology, Postgraduate Medical School, Warsaw 01-813, Poland. fedna@cmkp.edu.pl.
authors.forename: Natalia
authors.initials: N
authors.lastname: Fedoryszak-Kuśka
authors.affiliation: Department of Clinical Physiology, Postgraduate Medical School, Warsaw 01-813, Poland. aberesew@cmkp.edu.pl.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Beręsewicz
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1