caa a22 4500 378920073 CHVBK 20180305123603.0 cr unu---uuuuu 161128e20040413xx s 000 0 eng 10.1515/BC.2004.014 doi (NATIONALLICENCE)gruyter-10.1515/BC.2004.014 O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide [Elektronische Daten] [S. L. Archer, X.-C. Wu, B. Thébaud, R. Moudgil, K. Hashimoto, E.D. Michelakis] The ductus arteriosus (DA) is a fetal artery that allows blood ejected from the right ventricle to bypass the pulmonary circulation in utero. At birth, functional closure of the DA is initiated by an O2-induced, vasoconstrictor mechanism which, though modulated by endothelialderived endothelin and prostaglandins, is intrinsic to the smooth muscle cell (DASMC) [Michelakis et al., Circ. Res. 91 (2002); pp. 478-486]. As pO2 increases, a mitochondrial O2-sensor (electron transport chain complexes I or III) is activated, which generates a diffusible redox mediator (H2O2). H2O2 inhibits voltagegated K+ channels (Kv) in DASMC. The resulting membrane depolarization activates Ltype Ca2+ channels, thereby promoting vasoconstriction. Conversely, inhibiting mitochondrial ETC complexes I or III mimics hypoxia, depolarizing mitochondria, and decreasing H2O2 levels. The resulting increase in K+ current hyperpolarizes the DASMC and relaxes the DA. We have developed two models for study of the DAs O2-sensor pathway, both characterized by decreased O2-constriction and Kv expression: (i) preterm rabbit DA, (ii) ionicallyremodeled, human term DA. The O2-sensitive channels Kv1.5 and Kv2.1 are important to DA O2-constriction and overexpression of either channel enhances DA constriction in these models. Understanding this O2-sensing pathway offers therapeutic targets to modulate the tone and patency of human DA in vivo, thereby addressing a common form of congenital heart disease in preterm infants. Copyright © 2004 by Walter de Gruyter GmbH & Co. KG Biochemistry nationallicence Molecular biology nationallicence Cellular biology nationallicence Archer S. L. aut Wu X.-C aut Thébaud B. aut Moudgil R. aut Hashimoto K. aut Michelakis E.D. aut Biological Chemistry Walter de Gruyter 385/3-4(2004-04-13), 205-216 1431-6730 385:3-4<205 2004 385 bchm https://doi.org/10.1515/BC.2004.014 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1515/BC.2004.014 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Archer S. L. aut NATIONALLICENCE 700 1- Wu X.-C aut NATIONALLICENCE 700 1- Thébaud B. aut NATIONALLICENCE 700 1- Moudgil R. aut NATIONALLICENCE 700 1- Hashimoto K. aut NATIONALLICENCE 700 1- Michelakis E.D. aut NATIONALLICENCE 773 0- Biological Chemistry Walter de Gruyter 385/3-4(2004-04-13), 205-216 1431-6730 385:3-4<205 2004 385 bchm CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter