O2 sensing in the human ductus arteriosus -: Regulation of voltage-gated K+ channels in smooth muscle cells by a mitochondrial redox sensor

被引:130
作者
Michelakis, ED
Rebeyka, I
Wu, XC
Nsair, A
Thébaud, B
Hashimoto, K
Dyck, JRB
Haromy, A
Harry, G
Barr, A
Archer, SL
机构
[1] Univ Alberta, Dept Med, Div Cardiol, Heart & Stroke Chair Cardiovasc Res, Edmonton, AB T6G 2B7, Canada
[2] Univ Alberta, Dept Med, Vasc Biol Grp, Edmonton, AB T6G 2B7, Canada
[3] Univ Alberta, Div Cardiac Surg, Edmonton, AB T6G 2B7, Canada
[4] Univ Alberta, Cardiovasc Res Grp, Edmonton, AB T6G 2B7, Canada
[5] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2B7, Canada
关键词
Kv2.1; Kv1.5; mitochondrial membrane potential; redox; hydrogen peroxide;
D O I
10.1161/01.RES.0000035057.63303.D1
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by 0, constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that 02 alters the function of an 02 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). O-2 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 O-2 cause similar constriction and K+ current inhibition (I-K). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased 0, and 4-AP constriction in DA rings and reduced O-2- and 4-AP-sensitive I-K in DASMCs. Remodeled DAMSCs are depolarized and express less O-2-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 0,. In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing I-K and reversing constriction to 02, but not phenylephrine. 02 increases, whereas hypoxia and ETC inhibitors decrease H,02 production by altering mitochondrial membrane potential (Deltapsim). H2O2, like O-2, inhibits I-K and depolarizes DASMCs. We conclude that O-2, controls human DA tone by modulating the function of the mitochondrial ETC thereby varying Deltapsim and the production of H2O2, which regulates DASMC Kv channel activity and DA tone.
引用
收藏
页码:478 / 486
页数:9
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