This Article Full Text Full Text (PDF) Data Supplement Data Supplement All Versions of this Article: 103/6/580    most recent CIRCRESAHA.108.171835v1 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 Briggs, L. E. Articles by Kasahara, H. Search for Related Content PubMed PubMed Citation Articles by Briggs, L. E. Articles by Kasahara, H. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Related Collections Other heart failure Arrythmias-basic studies Physiological and pathological control of gene expression

(Circulation Research. 2008;103:580.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Perinatal Loss of Nkx2-5 Results in Rapid Conduction and Contraction Defects

Laura E. Briggs^*, Morihiko Takeda^*, Adolfo E. Cuadra^*, Hiroko Wakimoto^*, Melissa H. Marks, Alexandra J. Walker, Tsugio Seki, Suk P. Oh, Jonathan T. Lu, Colin Sumners, Mohan K. Raizada, Nobuo Horikoshi, Ellen O. Weinberg, Kenji Yasui, Yasuhiro Ikeda, Kenneth R. Chien, Hideko Kasahara

From the Department of Physiology and Functional Genomics (L.E.B., M.T., A.E.C., M.H.M., A.J.W., T.S., S.P.O., C.S., M.K.R., H.K.), University of Florida College of Medicine, Gainesville; Department of Pediatrics and Developmental Biology (H.W.), Graduate School of Medicine, Tokyo Medical and Dental University, Japan; Cardiology Division (J.T.L.), University of California, San Francisco; Department of Radiation Oncology (N.H.), Washington University School of Medicine, St Louis, Mo; Cardiovascular Research (E.O.W.), Boston University Medical Center, Mass; Department of Bioinformation Analysis (K.Y.), Research Institute of Environmental Medicine, Nagoya University, Aichi, Japan; Department of Molecular Cardiovascular Biology (Y.I.), Yamaguchi University School of Medicine, Ube, Japan; and Cardiovascular Research Center (K.R.C.), Massachusetts General Hospital, Boston.

Correspondence to Hideko Kasahara, MD, PhD, University of Florida College of Medicine, 1600 SW Archer Rd, M-540, Gainesville, FL 32610-0274. E-mail hkasahar{at}phys.med.ufl.edu

Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na⁺ channel pore-forming -subunit (Na_v1.5-), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca²⁺ for contraction (conduction–contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca²⁺ is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.

Key Words: conduction • contraction • gene targeting • transcription

This article has been cited by other articles:

				C. J. Hatcher and C. T. Basson Specification of the Cardiac Conduction System by Transcription Factors Circ. Res., September 25, 2009; 105(7): 620 - 630. [Abstract] [Full Text] [PDF]