Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure

Abstract

Background Human heart failure (HF) 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 HF. 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 HF and a specific splicing pathway for SCN5A regulation were explored in this paper. 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 (hESC-CMs). 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 HF, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full length Na+ channel transcript. Since 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.

Circulation: Heart Failure Editors' Picks

“…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. 3 Summary: The clinical benefit of cardiac resynchronization therapy for patients with moderate to severe symptomatic heart failure, severe left ventricular systolic dysfunction, and intraventricular conduction delay is firmly established. Nonetheless, a significant number of patients derive limited benefit from cardiac resynchronization therapy.…”

The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association

“…44 Microarray analysis of normal versus failing human myocardium identified upregulation in specific splicing factors in heart failure that led to increased levels of a truncated, nonfunctional version of SCN5A that reduces sodium current. 45 Interestingly, aberrant SCN5A splicing is also observed in peripheral blood cells from patients with heart failure and is tightly correlated with myocardial SCN5A mRNA levels, thus providing a peripheral blood "window" into the electric properties of the heart. 46 Peripheral blood SCN5A expression profiling with PCR predicted appropriate ICD shock therapy in patients with heart failure with high accuracy.…”

Circulation Editors' Picks

“…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. 18 …”