Journal article
Oxygen Activates the Rho/Rho-Kinase Pathway and Induces RhoB and ROCK-1 Expression in Human and Rabbit Ductus Arteriosus by Increasing Mitochondria-Derived Reactive Oxygen Species: A Newly Recognized Mechanism for Sustaining Ductal Constriction
Circulation (New York, N.Y.), Vol.115(13), pp.1777-1788
04/03/2007
DOI: 10.1161/CIRCULATIONAHA.106.649566
PMID: 17353442
Abstract
Background—
Constriction of the ductus arteriosus (DA) is initiated at birth by inhibition of O
2
-sensitive K
+
channels in DA smooth muscle cells. Subsequent membrane depolarization and calcium influx through L-type calcium channels initiates functional closure. We hypothesize that Rho-kinase activation is an additional mechanism that sustains DA constriction.
Methods and Results—
The effect of increased P
o
2
on the activity and expression of Rho-kinase was assessed in DAs from neonates with hypoplastic left-heart syndrome (n=15) and rabbits (339 term and 99 preterm rabbits). Rho-kinase inhibitors (Y-27632 and fasudil) prevent and reverse O
2
constriction. Heterogeneity exists in the sensitivity of constrictors (P
o
2
=endothelin=phenylephrine>KCl) and of fetal vessels (DA=pulmonary artery>aorta) to Rho-kinase inhibition. Inhibition of L-type calcium channels (nifedipine) or removal of extracellular calcium inhibits approximately two thirds of O
2
constriction. Residual DA constriction reflects calcium sensitization, which persists after removal of extracellular calcium and blocking of sarcoplasmic reticulum Ca
2+
-ATPase. In term DA, an increase in P
o
2
activates Rho-kinase and thereby increases RhoB and ROCK-1 expression. Activation of Rho-kinase in DA smooth muscle cells is initiated by a P
o
2
-dependent, rotenone-sensitive increase in mitochondrion-derived reactive O
2
species. O
2
effects on Rho-kinase are mimicked by exogenous H
2
O
2
. In preterm DAs, immaturity of mitochondrial reactive oxygen species generation is associated with reduced and delayed O
2
constriction and lack of P
o
2
-dependent upregulation of Rho-kinase expression.
Conclusions—
O
2
activates Rho-kinase and increases Rho-kinase expression in term DA smooth muscle cells by a redox-regulated, positive-feedback mechanism that promotes sustained vasoconstriction. Conversely, Rho-kinase inhibitors may be useful in maintaining DA patency, as a bridge to congenital heart surgery.
Details
- Title: Subtitle
- Oxygen Activates the Rho/Rho-Kinase Pathway and Induces RhoB and ROCK-1 Expression in Human and Rabbit Ductus Arteriosus by Increasing Mitochondria-Derived Reactive Oxygen Species: A Newly Recognized Mechanism for Sustaining Ductal Constriction
- Creators
- Hidemi Kajimoto - University of AlbertaKyoko Hashimoto - University of AlbertaSandra N. Bonnet - Tokyo Women's Medical UniversityAlois Haromy - Tokyo Women's Medical UniversityGwyneth Harry - Tokyo Women's Medical UniversityRohit Moudgil - Tokyo Women's Medical UniversityToshio Nakanishi - University of AlbertaIvan Rebeyka - Tokyo Women's Medical UniversityBernard Thébaud - Tokyo Women's Medical UniversityEvangelos D. Michelakis - Tokyo Women's Medical UniversityStephen L. Archer - Tokyo Women's Medical University
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.115(13), pp.1777-1788
- DOI
- 10.1161/CIRCULATIONAHA.106.649566
- PMID
- 17353442
- NLM abbreviation
- Circulation
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Number of pages
- 12
- Language
- English
- Date published
- 04/03/2007
- Academic Unit
- Cardiology; Stead Family Department of Pediatrics
- Record Identifier
- 9984961114302771
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