This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 110/11/1372    most recent 01.CIR.0000141292.28616.65v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thébaud, B. Articles by Archer, S. L. Search for Related Content PubMed PubMed Citation Articles by Thébaud, B. Articles by Archer, S. L. Related Collections Animal models of human disease Developmental biology Ion channels/membrane transport Pulmonary circulation and disease Gene therapy Other Vascular biology

(Circulation. 2004;110:1372-1379.)
© 2004 American Heart Association, Inc.

Original Articles

Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus

Implications for Infants With Patent Ductus Arteriosus

Bernard Thébaud, MD PhD; Evangelos D. Michelakis, MD; Xi-Chen Wu, PhD; Rohit Moudgil, MSc; Michael Kuzyk, PhD; Jason R.B. Dyck, PhD; Gwyneth Harry, MSc; Kyoko Hashimoto, BSc; Alois Haromy, BSc; Ivan Rebeyka, MD; Stephen L. Archer, MD

From the Vascular Biology Group (B.T., E.D.M., X.-C.W., R.M., J.R.B.D., G.H., K.H., A.H., S.L.A.), Department of Physiology (S.L.A.), Department of Pediatrics (B.T., J.R.B.D.), Cardiovascular Research Group and Department of Pharmacology (J.R.B.D.), and Division of Cardiovascular Surgery (I.R.), University of Alberta, Edmonton, Alberta, Canada; and Ciphergen Biosystems Inc (M.K.), Freemont, Calif.

Correspondence to Dr Stephen Archer, Cardiology, University of Alberta, 2C2.36 Walter Mackenzie Health Sciences Center, Edmonton, Alberta, Canada T6G 2B7. E-mail sarcher{at}cha.ab.ca

Received December 13, 2003; revision received April 1, 2004; accepted April 16, 2004.

Background— Oxygen (O₂)-sensitive K⁺ channels mediate acute O₂ sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O₂-induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O₂ constriction in preterm DA is reduced expression and function of O₂-sensitive, voltage-gated (Kv) channels.

Methods and Results— Preterm rabbit DA rings have reduced O₂ constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O₂-sensitive K⁺ current. This is associated with decreased mRNA and protein expression of certain O₂-sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer "rescues" the developmental deficiency, conferring O₂ responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O₂ constriction in human DAs.

Conclusions— These data demonstrate a central role for developmentally regulated DASMC O₂-sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O₂ responsiveness, including persistent DA.

Key Words: gene therapy • heart defects, congenital • oxygen sensing • viruses

This article has been cited by other articles:

				T. Vaithianathan, A. Bukiya, J. Liu, P. Liu, M. Asuncion-Chin, Z. Fan, and A. Dopico Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway J. Gen. Physiol., June 30, 2008; 132(1): 13 - 28. [Abstract] [Full Text] [PDF]

				R. I. Clyman, N. Waleh, H. Kajino, C. Roman, and F. Mauray Calcium-dependent and calcium-sensitizing pathways in the mature and immature ductus arteriosus Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1650 - R1656. [Abstract] [Full Text] [PDF]

				H. Kajimoto, K. Hashimoto, S. N. Bonnet, A. Haromy, G. Harry, R. Moudgil, T. Nakanishi, I. Rebeyka, B. Thebaud, E. D. Michelakis, et al. 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, April 3, 2007; 115(13): 1777 - 1788. [Abstract] [Full Text] [PDF]

				Z. Hong, F. Hong, A. Olschewski, J. A. Cabrera, A. Varghese, D. P. Nelson, and E. K. Weir Role of Store-Operated Calcium Channels and Calcium Sensitization in Normoxic Contraction of the Ductus Arteriosus Circulation, September 26, 2006; 114(13): 1372 - 1379. [Abstract] [Full Text] [PDF]

				E. K. Weir and A. Olschewski Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia Cardiovasc Res, September 1, 2006; 71(4): 630 - 641. [Abstract] [Full Text] [PDF]

				E. Miguel-Velado, A. Moreno-Dominguez, O. Colinas, P. Cidad, M. Heras, M. T. Perez-Garcia, and J. R. Lopez-Lopez Contribution of Kv Channels to Phenotypic Remodeling of Human Uterine Artery Smooth Muscle Cells Circ. Res., December 9, 2005; 97(12): 1280 - 1287. [Abstract] [Full Text] [PDF]

				M. Keck, E. Resnik, B. Linden, F. Anderson, D. J. Sukovich, J. Herron, and D. N. Cornfield Oxygen increases ductus arteriosus smooth muscle cytosolic calcium via release of calcium from inositol triphosphate-sensitive stores Am J Physiol Lung Cell Mol Physiol, May 1, 2005; 288(5): L917 - L923. [Abstract] [Full Text] [PDF]