Abstract 11842: Meis1 Transcriptionally Regulates the Expression of NaV1.5 Protein
Introduction: Genome-wide association studies have identified loci associated with cardiac conduct system (CCS) function, including Meis1. Meis1, a transcription factor, plays a critical role in the regulation of cardiac differentiation and proliferation. Mechanisms of Meis1 linked to CCS function are unknown.
Hypothesis: We hypothesized that Meis1 regulates NaV1.5 expression by affecting SCN5a promoter activity and plays important roles in the regulation of CCS function and development of arrhythmias in myocardial infarction (MI).
Methods: In silico promoter analysis was performed to determine if SCN5a promoter harbors Meis1 conservative binding sites. Luciferase reporter assay was done to determine effects of Meis1 on SCN5a promoter activity in HeLa cells infected with adenovirus-Meis1 or transfected with siRNA targeting Meis1. qRT-PCR and Western blot were employed to determine effects of Meis1 on NaV1.5 or H2O2 on Meis1 expression, and they were used to determine NaV1.5 and Meis1 levels in peri-infarct zone (PIZ) of mouse hearts with MI induced by ligation of left anterior descending coronary artery. Whole-cell Na+ currents were recorded from HL-1 cells expressing Meis1.
Results: In silico promoter analysis revealed that SCN5a promoter contains Meis1 conservative binding sites in humans, mice and rats. Luciferase reporter assay showed that SCN5a promoter activity was increased by expression of Meis1 and was decreased by knockdown of Meis1 decreased in HeLa cells. Expression of Meis1 increased NaV1.5 mRNA without affecting β subunits, and augmented NaV1.5 protein and Na+ current density in HL-1 cells. Meis1 and NaV1.5 mRNA and protein were significantly decreased in PIZ after MI for one week, compared to sham group. In HL-1 cells treated with 200 μM H2O2 for one hour, NaV1.5 and Meis1 mRNA and protein were significantly decreased, compared to control group.
Conclusions: Meis1 transcriptionally upregulates NaV1.5 expression by increasing SCN5a promoter activity and downregulation of Meis1 leads to NaV1.5 reduction in MI. Our findings indicate that Meis1 plays important roles by regulating NaV1.5 expression in the maintenance of CCS function and development of arrhythmias in MI.
Author Disclosures: N. Wang: None. Y. Lu: None. B. Ye: None. X. Li: None. T. You: None. F. Li: None. H. Xu: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.