Published online before print August 29, 2002, doi: 10.1161/01.RES.0000035057.63303.D1
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Submitted on November 15, 2001
Revised on August 13, 2002
Accepted on August 15, 2002
O2 Sensing in the Human Ductus Arteriosus. Regulation of Voltage-Gated K+ Channels in Smooth Muscle Cells by a Mitochondrial Redox Sensor
Evangelos D. Michelakis ;
From the Cardiology Division and the Vascular Biology Group, Department of Medicine (E.D.M., X.W., A.N., B.T., K.H., J.R.B.D., A.H., G.H., S.L.A.), the Division of Cardiac Surgery (I.R., A.B.), and the Department of Physiology (S.L.A.), University of Alberta, Alberta, Canada.
* To whom correspondence should be addressed. E-mail: sarcher{at}cha.ab.ca.
Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by O2 constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that O2 alters the function of an O2 sensor (the mitochondrial electron transport chain, ETC) thereby increasing production of a diffusible redox-mediator (H2O2), thus triggering an effector mechanism (inhibition of DASMC voltage-gated K+ channels, Kv). O2 constriction was evaluated in 26 human DAs (12 female, aged 9±2 days) studied in their normal hypoxic state or after normoxic tissue culture. In fresh, hypoxic DAs, 4-aminopyridine (4-AP), a Kv inhibitor, and O2 cause similar constriction and K+ current inhibition (IK). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased O2 and 4-AP constriction in DA rings and reduced O2- and 4-AP-sensitive IK in DASMCs. Remodeled DAMSCs are depolarized and express less O2-sensitive channels (including Kv2.1, Kv1.5, Kv9.3, Kv4.3, and BKCa). Kv2.1 adenoviral gene-transfer significantly reverses ionic remodeling, partially restoring both the electrophysiological and tone responses to 4-AP and O2. In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing IK and reversing constriction to O2, but not phenylephrine. O2 increases, whereas hypoxia and ETC inhibitors decrease H2O2 production by altering mitochondrial membrane potential (
m). H2O2, like O2, inhibits IK and depolarizes DASMCs. We conclude that O2 controls human DA tone by modulating the function of the mitochondrial ETC thereby varying m and the production of H2O2, which regulates DASMC Kv channel activity and DA tone.
Key words: O2 sensing • Kv2.1 • Kv1.5 • mitochondrial membrane potential • redox • hydrogen peroxide • gene transfer • TMRM • JC-1
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