TY - JOUR
T1 - O2 sensing in the human ductus arteriosus
T2 - Redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide
AU - Archer, Stephen L.
AU - Wu, Xi Chen
AU - Thébaud, Bernard
AU - Moudgil, Rohit
AU - Hashimoto, Kyoto
AU - Michelakis, Evangelos D.
N1 - Funding Information:
Both E.D. Michelakis and S.L. Archer are supported by the Alberta Heritage Foundation for Medical Research (AHFMR), the Canadian Foundation for Innovation and the Heart and Stroke Foundation of Canada and the Canadian Institutes for Health Research (CIHR). Dr Archer is the Heart and Stroke Foundation Chair for Cardiovascular Research for Northern Alberta. Dr. Thé-baud is supported by grants from CIHR and AHFMR.
PY - 2004/3
Y1 - 2004/3
N2 - 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 endothelial-derived 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 voltage-gated K+ channels (Kv) in DASMC. The resulting membrane depolarization activates L-type 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 DA's O2-sensor pathway, both characterized by decreased O2-constriction and Kv expression: (i) preterm rabbit DA, (ii) ionically-remodeled, 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.
AB - 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 endothelial-derived 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 voltage-gated K+ channels (Kv) in DASMC. The resulting membrane depolarization activates L-type 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 DA's O2-sensor pathway, both characterized by decreased O2-constriction and Kv expression: (i) preterm rabbit DA, (ii) ionically-remodeled, 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.
KW - Adenoviral gene therapy
KW - Kv channels
KW - Laser capture microdissection
KW - Mitochondrial electron transport chain
KW - Protein chip
KW - Redox
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U2 - 10.1515/BC.2004.014
DO - 10.1515/BC.2004.014
M3 - Review article
C2 - 15134333
AN - SCOPUS:2542435891
SN - 1431-6730
VL - 385
SP - 205
EP - 216
JO - Biological Chemistry
JF - Biological Chemistry
IS - 3-4
ER -