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Sex Differences in Ion-Channel Promoter Expression of Healthy Human Heart Open Access

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Background: Cardiovascular diseases remain the primary cause of death worldwide. Several epidemiologic and investigative studies have shown the evidence of sex hormones effect on cardiac electrophysiology through genomic regulation. However, very little is known about the molecular basis for gender-related discrepancies in cardiac electrophysiology. Due to physiologically distinct functions of atria (electrical impulse initiation) and ventricles (blood pumping) there is a difference in ion-channel expression within a heart that cause different disease susceptibilities between both sexes. Objective: Compare holistic ion-channel gene expression associated with sex differences using Cap Analysis of Gene Expression (CAGE) analysis on left atrial (LA) and left ventricular (LV) human donor hearts. Methods: Total RNA was extracted from left atria (LA) and left ventricle (LV) of human donor hearts n=4 males (mean age = 53.75) and n=3 females (mean age = 58.7), the cause of death was determined to be non-cardiogenic. Samples were analyzed with CAGE, which is a high throughput method for transcriptome analysis that utilizes "cap-trapping'. The number of tags gives a frequency of usage that provides information about transcription start sites as well as transcript expression levels. Normalization of raw CAGE tag count was performed as counts per million. Statistical significance (p<0.05) was determined with Wilcoxon Rank-Sum and Kruskal-Wallis tests. Results: 57 genes are known to code for ion-channel I+-- and I^2-subunits in human hearts. Interestingly, 14 genes were not detectable; 13 genes showed low expression which was insufficient for promoter identification with the threshold of +/-500 bp regions. Male and female ion-channel expression levels were significantly different from each other (p=0.0002). The highest upregulation in both sexes was detected in promoters of INa (SCN5A and SCN1B), Ito,f (KCNIP2), IK2P (KCNK1), and INCX (SLC8A1). Interestingly, SLC8A1, which is known to be cardioprotective from ischemic injury was significantly upregulated in female atrium (p= 0.0408). Other promoter expression that was significantly different across sexes include: Ito,f (KCND3) (p=0.0186) and IKATP (KCNJ11) (p=0.049) in atrium and INa (SCN4B) (p=0.028) in ventricle. Conclusion: Our study reveals that there are sex-dependent gene expression differences in cardiac ion-channels and that CAGE approach allows high-throughput gene expression profiling which can be beneficial for gender-specific computational model development, drug testing, and personalized medicine overall.

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