The Role of Genome Regulatory Network in Sex Dimorphism of Cardiac Health, Disease, and Aging
Open AccessThe prevalence of cardiovascular diseases differs between men and women. For example, men are more likely to develop hypertrophic and dilated cardiomyopathies, whereas women are prone to experience Takotsubo cardiomyopathy and long QT syndrome. Surprisingly, it is not clear what causes those differences in disease susceptibilities. Until recently, clinical trials were predominantly performed on males, and experimental studies mostly utilized male animals due to ‘messy’ female biology. Males and females have distinct sex chromosomes and sex hormone composition. These variables were shown to contribute towards differences in gene expression and cardiac electrophysiology.This dissertation investigates the basis of the genomic regulation and hormonal influences responsible for sex differences in the human heart to reveal why certain pathologies originate in males and females. First, using RNA sequencing and optical mapping techniques, I established the experimental methodology and showed genomic and electrophysiological changes happening in rat pacemaker regions during heart failure. The functional quiescence of 1 out of 2 pacemakers was due to the genetic downregulation of key ion channels, structural genes, and transcription factors. Animal models are useful for methodology development, yet they still present limitations and discrepancies when translating findings to humans. Therefore, I optically mapped cardiac slices from human donor hearts to elucidate baseline sex differences in cardiac electrophysiology and applied sex hormones to investigate changes in transmembrane potentials and calcium transients. I detected action potential morphology differences between males and females. Moreover, most sex hormone-related changes affected excitation-contraction coupling. Next, I used tissues from healthy and failing human hearts to create and validate an atlas of cardiac regulatory elements: promoters and enhancers. This atlas serves as an online platform to study transcribed regulatory elements in all four cardiac chambers. Finally, using this database, I identified numerous promoters and enhancers specific to each sex and genomic regulation change due to disease and aging. Sex differences were mostly linked to the immune system, metabolic, and developmental functions. This work reveals the effects of sex-specific genomic regulation and sex differences in cardiac function to allow the development of more appropriate sex-specific therapies.
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