O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide
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S. L. Archer
Abstract
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
Articles in the same Issue
- Oxygen and the Cell
- O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide
- Oxidative stress in the systemic and cellular responses to intermittent hypoxia
- HIF hydroxylation and cellular oxygen sensing
- Visualization of the three-dimensional organization of hypoxia-inducible factor-1α and interacting cofactors in subnuclear structures
- Modulation of glucokinase expression by hypoxia-inducible factor 1 and upstream stimulatory factor 2 in primary rat hepatocytes
- Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells
- Measurement of exhaled hydrogen peroxide from rabbit lungs
- Effects of reducing agents on glutathione metabolism and the function of carotid body chemoreceptor cells
- Expression of functional purinergic receptors in pulmonary neuroepithelial bodies and their role in hypoxia chemotransmission
- Remodelling of Ca2+ homeostasis in type I cortical astrocytes by hypoxia: evidence for association with Alzheimer's disease
- Simultaneous exposure of rats to dioxin and carbon monoxide reduces the xenobiotic but not the hypoxic response
- Structure and expression of two kininogen genes in mice
- The central domain of the matrix protein of HIV-1: influence on protein structure and virus infectivity
- Skin secretion of the toad Bombina variegata contains multiple insulin-releasing peptides including bombesin and entirely novel insulinotropic structures
- Inhibition of lentil copper/TPQ amine oxidase by the mechanism-based inhibitor derived from tyramine
- Enhanced expression of basolateral multidrug resistance protein isoforms Mrp3 and Mrp5 in rat liver by LPS
- Critical O2 and NO concentrations in NO-induced cell death in a rat liver sinusoidal endothelial cell line
Articles in the same Issue
- Oxygen and the Cell
- O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide
- Oxidative stress in the systemic and cellular responses to intermittent hypoxia
- HIF hydroxylation and cellular oxygen sensing
- Visualization of the three-dimensional organization of hypoxia-inducible factor-1α and interacting cofactors in subnuclear structures
- Modulation of glucokinase expression by hypoxia-inducible factor 1 and upstream stimulatory factor 2 in primary rat hepatocytes
- Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells
- Measurement of exhaled hydrogen peroxide from rabbit lungs
- Effects of reducing agents on glutathione metabolism and the function of carotid body chemoreceptor cells
- Expression of functional purinergic receptors in pulmonary neuroepithelial bodies and their role in hypoxia chemotransmission
- Remodelling of Ca2+ homeostasis in type I cortical astrocytes by hypoxia: evidence for association with Alzheimer's disease
- Simultaneous exposure of rats to dioxin and carbon monoxide reduces the xenobiotic but not the hypoxic response
- Structure and expression of two kininogen genes in mice
- The central domain of the matrix protein of HIV-1: influence on protein structure and virus infectivity
- Skin secretion of the toad Bombina variegata contains multiple insulin-releasing peptides including bombesin and entirely novel insulinotropic structures
- Inhibition of lentil copper/TPQ amine oxidase by the mechanism-based inhibitor derived from tyramine
- Enhanced expression of basolateral multidrug resistance protein isoforms Mrp3 and Mrp5 in rat liver by LPS
- Critical O2 and NO concentrations in NO-induced cell death in a rat liver sinusoidal endothelial cell line
