Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure

Ge Gao, An Xie, Shu Ching Huang, Anyu Zhou, Jianhua Zhang, Amanda M. Herman, Sassan Ghassemzadeh, Euy Myoung Jeong, Srinivasan Kasturirangan, Mihai Raicu, Michael A. Sobieski, Geetha Bhat, Antone Tatooles, Edward J. Benz, Timothy J. Kamp, Samuel C. Dudley

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

BACKGROUND-: Human heart failure is associated with decreased cardiac voltage-gated Na channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study. METHODS AND RESULTS-: Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes. RBM25/LUC7L3- mediated abnormal SCN5A mRNA splicing reduced Na channel current 91.1±9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript. CONCLUSIONS-: Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure.

Original languageEnglish (US)
Pages (from-to)1124-1131
Number of pages8
JournalCirculation
Volume124
Issue number10
DOIs
StatePublished - Sep 6 2011

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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