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Int. J. Mol. Sci. 2014, 15(11), 19417-19443; doi:10.3390/ijms151119417

Obligatory Role of Intraluminal O2 in Acute Endothelin-1 and Angiotensin II Signaling to Mediate Endothelial Dysfunction and MAPK Activation in Guinea-Pig Hearts

Department of Clinical Physiology, Postgraduate Medical School, Warsaw 01-813, Poland
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Received: 5 August 2014 / Revised: 30 September 2014 / Accepted: 8 October 2014 / Published: 27 October 2014
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2015)
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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. View Full-Text
Keywords: oxidative stress; endothelin-1; angiotensin-II; endothelial dysfunction; mitogen-activated protein kinases; mitochondria; NADPH-oxidase; xanthine oxidase; guinea-pig heart oxidative stress; endothelin-1; angiotensin-II; endothelial dysfunction; mitogen-activated protein kinases; mitochondria; NADPH-oxidase; xanthine oxidase; guinea-pig heart
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Wojtera, E.; Konior, A.; Fedoryszak-Kuśka, N.; Beręsewicz, A. Obligatory Role of Intraluminal O2 in Acute Endothelin-1 and Angiotensin II Signaling to Mediate Endothelial Dysfunction and MAPK Activation in Guinea-Pig Hearts. Int. J. Mol. Sci. 2014, 15, 19417-19443.

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