TY - JOUR
T1 - Molecular basis of funny current (If) in normal and failing human heart
AU - Stillitano, Francesca
AU - Lonardo, Giuseppe
AU - Zicha, Stephen
AU - Varro, Andras
AU - Cerbai, Elisabetta
AU - Mugelli, Alessandro
AU - Nattel, Stanley
N1 - Funding Information:
The financial support of Minister of Education, University and Research (PRIN 2006), Telethon (Grant GGP05093) and Ente Cassa di Risparmio di Firenze, Italy and of the Canadian Institutes of Health Research, is gratefully acknowledged. We wish to acknowledge the support of the Normacor Partners (contract LSH M/CT/2006/018676) and particularly Prof. Martin Biel (University of Munich, Germany) for providing stably transfected HCN2 and HCN4 HEK293 cells.
PY - 2008/8
Y1 - 2008/8
N2 - If overexpression has been functionally demonstrated in ventricular myocytes from failing human hearts. Altered expression of If-channels as a consequence of electrophysiological remodeling may represent an arrhythmogenic mechanism in heart failure; however, the molecular basis of If overexpression in human cardiac disease is unknown. HCN1, 2 and 4 subtypes, which encode If-channels, have been identified in the heart. The present study was designed to characterize HCN isoform expression in failing and non-failing hearts. Ventricular and atrial samples were obtained from normal or failing hearts explanted from patients with end-stage ischemic cardiomyopathy. If was recorded in patch-clamped left ventricular myocytes. mRNA and protein expression of HCN subunits were measured in both atria and ventricles of control and diseased hearts. HCN2 and HCN4 were detected in human myocardium. Both mRNA and protein levels of HCN2/4 were significantly augmented in failing ventricles (p < 0.01 for mRNA, p < 0.05 for protein). These results are consistent with the electrophysiological data showing that, in failing ventricular myocytes, If is of larger amplitude and activates at less negative potential. Changes in mRNA and protein expression of both HCN2/4 isoforms in atrial specimens from patients with heart failure mirrored those observed in ventricles (p < 0.001 for mRNA, p < 0.05 for protein). No disease-dependent alteration was detected for MiRP1, the putative β-subunit of the If-channel. In conclusion, HCN4 is the predominant channel subtype in normal human heart, and its expression is further amplified by disease. HCN upregulation likely contributes to increased If and may play a role in ventricular and atrial arrhythmogenesis in heart failure.
AB - If overexpression has been functionally demonstrated in ventricular myocytes from failing human hearts. Altered expression of If-channels as a consequence of electrophysiological remodeling may represent an arrhythmogenic mechanism in heart failure; however, the molecular basis of If overexpression in human cardiac disease is unknown. HCN1, 2 and 4 subtypes, which encode If-channels, have been identified in the heart. The present study was designed to characterize HCN isoform expression in failing and non-failing hearts. Ventricular and atrial samples were obtained from normal or failing hearts explanted from patients with end-stage ischemic cardiomyopathy. If was recorded in patch-clamped left ventricular myocytes. mRNA and protein expression of HCN subunits were measured in both atria and ventricles of control and diseased hearts. HCN2 and HCN4 were detected in human myocardium. Both mRNA and protein levels of HCN2/4 were significantly augmented in failing ventricles (p < 0.01 for mRNA, p < 0.05 for protein). These results are consistent with the electrophysiological data showing that, in failing ventricular myocytes, If is of larger amplitude and activates at less negative potential. Changes in mRNA and protein expression of both HCN2/4 isoforms in atrial specimens from patients with heart failure mirrored those observed in ventricles (p < 0.001 for mRNA, p < 0.05 for protein). No disease-dependent alteration was detected for MiRP1, the putative β-subunit of the If-channel. In conclusion, HCN4 is the predominant channel subtype in normal human heart, and its expression is further amplified by disease. HCN upregulation likely contributes to increased If and may play a role in ventricular and atrial arrhythmogenesis in heart failure.
KW - Arrhythmias
KW - Electrophysiology
KW - Gene expression
KW - Human heart failure
KW - Hyperpolarization-activated Cyclin Nucleotide gated channel
KW - Ischemic cardiomyopathy
UR - http://www.scopus.com/inward/record.url?scp=48849089617&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2008.04.013
DO - 10.1016/j.yjmcc.2008.04.013
M3 - Article
C2 - 18556018
AN - SCOPUS:48849089617
SN - 0022-2828
VL - 45
SP - 289
EP - 299
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 2
ER -