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(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

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