Genetic mechanisms of cardiac sex diparities

ABSTRACT: Male and female disease states differ in their prevalence, treatment responses, and survival rates. In cardiac disease, women almost uniformly fare far worse than men1-3. Though sex plays a critical role in cardiac disease, the mechanisms underlying sex differences in cardiac homeostasis and disease remain unexplained. Here, we reveal sex-specific cardiac transcriptomes and proteomes and show that cardiac sex differences are predominately controlled via post-transcriptional mechanisms. Using a quantitative proteomics-based approach, we characterize differential sex-specific enriched cardiac proteins, protein complexes, and biological sex processes in the context of global genetic diversity of the Collaborative Cross. We show that differences in cardiac protein expression are established by both hormonal and genetic mechanisms and define two additional pathways, one that is SRY dependent and one that is SRY-independent. We also determined the onset of sex-biased protein expression and discovered that sex disparities in heart tissue occur at the earliest stages of heart development, during the period preceding primary mammalian sex determination. This may explain why congenital heart disease, a leading cause of death whose origin is often developmental, is sex biased. Our results reveal the molecular foundations for the differences in cardiac tissue that underlie sex disparities in health, disease, and treatment outcomes.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Xinlei Sheng  

LAB HEAD: Ileana M. Cristea

PROVIDER: PXD020139 | Pride | 2022-08-11

REPOSITORIES: Pride