Published online before print September 27, 2007, doi: 10.1161/CIRCRESAHA.107.152918
© 2007 American Heart Association, Inc.
Cellular Biology |
Human Heart Failure Is Associated With Abnormal C-Terminal Splicing Variants in the Cardiac Sodium Channel
From the Division of Cardiology (L.L.S., A.E.P., S.S., Z.J., J.A., D.W., W.R.T., A.M.Z., S.C.D.), Department of Medicine, Emory University, Atlanta, Ga; the Atlanta Veteran’s Affairs Medical Center (L.L.S., A.E.P., S.S., Z.J., J.A., D.W., W.R.T., A.M.Z., S.C.D.), Decatur, Ga; and Department of Physiology (K.B., J.F.), Loyola University Chicago, Maywood, Ill.
Correspondence to Dr Samuel C. Dudley, Jr, Section of Cardiology, University of Illinois at Chicago, 840 South Wood St (MC 715), Chicago, Illinois 60612. E-mail scdudley{at}uic.edu
Heart failure (HF) is associated with reduced cardiac Na+ channel (SCN5A) current. We hypothesized that abnormal transcriptional regulation of this ion channel during HF could help explain the reduced current. Using human hearts explanted at the transplantation, we have identified 3 human C-terminal SCN5A mRNA splicing variants predicted to result in truncated, nonfunctional channels. As compared with normal hearts, the explanted ventricles showed an upregulation of 2 of the variants and a downregulation of the full-length mRNA transcript such that the E28A transcript represented only 48.5% (P<0.01) of the total SCN5A mRNA. This correlated with a 62.8% (P<0.01) reduction in Na+ channel protein. Lymphoblasts and skeletal muscle expressing SCN5A also showed identical C-terminal splicing variants. Variants showed reduced membrane protein and no functional current. Transfection of truncation variants into a cell line stably transfected with the full-length Na+ channel resulted in dose-dependent reductions in channel mRNA and current. Introduction of a premature truncation in the C-terminal region in a single allele of the mouse SCN5A resulted in embryonic lethality. Embryonic stem cell–derived cardiomyocytes expressing the construct showed reductions in Na+ channel–dependent electrophysiological parameters, suggesting that the presence of truncated Na+ channel mRNA at levels seen in HF is likely to be physiologically significant. In summary, chronic HF was associated with an increase in 2 truncated SCN5A variants and a decrease in the native mRNA. These splice variations may help explain a loss of Na+ channel protein and may contribute to the increased arrhythmic risk in clinical HF.
Key Words: sodium channels • transcriptional regulation • mRNA splice variations • heart failure • arrhythmia
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