Transcriptome and Functional Profile of Cardiac Myocytes Is Influenced by Biological Sex.

ABSTRACT

BACKGROUND: Although cardiovascular disease is the primary killer of women in the United States, women and female animals have traditionally been omitted from research studies. In reports that do include both sexes, significant sexual dimorphisms have been demonstrated in development, presentation, and outcome of cardiovascular disease. However, there is little understanding of the mechanisms underlying these observations. A more thorough understanding of sex-specific cardiovascular differences both at baseline and in disease is required to effectively consider and treat all patients with cardiovascular disease. METHODS AND RESULTS: We analyzed contractility in the whole rat heart, adult rat ventricular myocytes (ARVMs), and myofibrils from both sexes of rats and observed functional sex differences at all levels. Hearts and ARVMs from female rats displayed greater fractional shortening than males, and female ARVMs and myofibrils took longer to relax. To define factors underlying these functional differences, we performed an RNA sequencing experiment on ARVMs from male and female rats and identified ≈600 genes were expressed in a sexually dimorphic manner. Further analysis revealed sex-specific enrichment of signaling pathways and key regulators. At the protein level, female ARVMs exhibited higher protein kinase A activity, consistent with pathway enrichment identified through RNA sequencing. In addition, activating the protein kinase A pathway diminished the contractile sexual dimorphisms previously observed. CONCLUSIONS: These data support the notion that sex-specific gene expression differences at baseline influence cardiac function, particularly through the protein kinase A pathway, and could potentially be responsible for differences in cardiovascular disease presentation and outcomes.