Copyright © 2005, European Society of Cardiology
Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model
aDepartments of Medicine and Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8
bDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
cUniversidad Complutense, Madrid, Spain
* Corresponding author. Departments of Medicine and Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger St E, Montreal, Quebec, H1T 1C8, Canada. Tel.: +1 514 376 3330x3990; fax: +1 514 376 1355. Email address: stanley.nattel{at}icm-mhi.org
Background: The hyperpolarization-activated cation current If contributes significantly to sinoatrial node pacemaker function and possibly to ectopic arrhythmogenesis. Little is known about the expression of corresponding hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits in normal hearts and HCN remodeling by diseases, like congestive heart failure (CHF), associated with disturbances of cardiac rhythm.
Methods and results: We assessed expression of HCN1, 2 and 4 in normal mongrel dogs and dogs subjected to 2-week ventricular tachypacing-induced CHF. Competitive RT-PCR, Western blot and immunohistochemistry were used to quantify HCN subunit mRNA and protein expression in the right atrium (RA) and sinoatrial node. CHF approximately doubled sinus node recovery time, indicating suppressed sinus node pacemaker function. HCN expression under control conditions was HCN4>HCN2>>HCN1. HCN2 and HCN4 expression was greater at both protein and mRNA levels in sinoatrial node than RA. CHF significantly decreased sinus node HCN expression at both mRNA and protein levels (HCN2 by 78% and 82%; HCN4 by 42% and 77%, respectively). RA HCN2 expression was unaltered by CHF, but HCN4 was significantly upregulated (by 209%).
Conclusions: HCN4 is the dominant subunit in canine sinoatrial node and RA; strong sinus node HCN expression likely contributes to its pacemaker function; downregulation of HCN4 and HCN2 expression contribute to CHF-induced sinus node dysfunction; and upregulation of atrial HCN4 may help to promote atrial arrhythmia formation. These findings provide novel information about the molecular basis of normal and disease-related impairments of cardiac impulse formation.
KEYWORDS Pacemaker current; Sinoatrial node; Congestive heart failure; Ion channels; Remodeling
Time for primary review 18 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y.-H. Yeh, B. Burstein, X. Y. Qi, M. Sakabe, D. Chartier, P. Comtois, Z. Wang, C.-T. Kuo, and S. Nattel Funny Current Downregulation and Sinus Node Dysfunction Associated With Atrial Tachyarrhythmia: A Molecular Basis for Tachycardia-Bradycardia Syndrome Circulation, March 31, 2009; 119(12): 1576 - 1585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Divakaran and D. L. Mann The Emerging Role of MicroRNAs in Cardiac Remodeling and Heart Failure Circ. Res., November 7, 2008; 103(10): 1072 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Mangoni and J. Nargeot Genesis and Regulation of the Heart Automaticity Physiol Rev, July 1, 2008; 88(3): 919 - 982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hardel, N. Harmel, G. Zolles, B. Fakler, and N. Klocker Recycling endosomes supply cardiac pacemaker channels for regulated surface expression Cardiovasc Res, July 1, 2008; 79(1): 52 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nattel, B. Burstein, and D. Dobrev Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications Circ Arrhythmia Electrophysiol, April 1, 2008; 1(1): 62 - 73. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Baruscotti and R. B. Robinson Electrophysiology and pacemaker function of the developing sinoatrial node Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2613 - H2623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. O. Verkerk, R. Wilders, M. M.G.J. van Borren, R. J.G. Peters, E. Broekhuis, K. Lam, R. Coronel, J. M.T. de Bakker, and H. L. Tan Pacemaker current (If) in the human sinoatrial node Eur. Heart J., October 2, 2007; 28(20): 2472 - 2478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ogawa, S. Zhou, A. Y. Tan, J. Song, G. Gholmieh, M. C. Fishbein, H. Luo, R. J. Siegel, H. S. Karagueuzian, L. S. Chen, et al. Left Stellate Ganglion and Vagal Nerve Activity and Cardiac Arrhythmias in Ambulatory Dogs With Pacing-Induced Congestive Heart Failure J. Am. Coll. Cardiol., July 24, 2007; 50(4): 335 - 343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fernandez-Velasco, G. Ruiz-Hurtado, O. Hurtado, M. A. Moro, and C. Delgado TNF-{alpha} downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H238 - H245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-K. Ju, Y. Chu, H. Chaulet, D. Lai, O. L. Gervasio, R. M. Graham, M. B. Cannell, and D. G. Allen Store-Operated Ca2+ Influx and Expression of TRPC Genes in Mouse Sinoatrial Node Circ. Res., June 8, 2007; 100(11): 1605 - 1614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Dobrzynski, M. R. Boyett, and R. H. Anderson New Insights Into Pacemaker Activity: Promoting Understanding of Sick Sinus Syndrome Circulation, April 10, 2007; 115(14): 1921 - 1932. [Full Text] [PDF]
|
|
|
|
|
|
S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, H. Dobrzynski, J. Yanni, M. R. Boyett, and M. Lei Organisation of the mouse sinoatrial node: structure and expression of HCN channels Cardiovasc Res, March 1, 2007; 73(4): 729 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Maguy, T. E. Hebert, and S. Nattel Involvement of lipid rafts and caveolae in cardiac ion channel function Cardiovasc Res, March 1, 2006; 69(4): 798 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. R. Giles Supraventricular pacemaker activity in the canine heart: Contributions from HCN channels in control conditions and in a model of heart failure Cardiovasc Res, June 1, 2005; 66(3): 430 - 432. [Full Text] [PDF]
|
|