Sex Differences in Regulating the Cardiac Transcriptome within a Murine Model for Hypertrophic Cardiomyopathy

Abstract

Heart disease remains the number one killer of women in the United States. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Susceptibility to hereditary hypertrophic cardiomyopathy, the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants. Among the susceptible genes, TNNC1—encoding cardiac troponin C (cTnC)—has contributed to a substantial hypertrophic cardiomyopathy (HCM) phenotype in mice. In this study we sought to characterize the sexual dimorphism observed within cardiac hemodynamics, morphology, and gene expression of a TNNC1 HCM mouse model. Adult age-matched male and female mice bearing the knock-in HCM-associated point mutation of alanine to valine in position 8 of cTnC (-A8V) were studied. The hemodynamics and cardiac morphology of the HCM mice were significantly altered. Isovolumetric contraction time was significantly higher in the female HCM mice, and female measurements for the majority of parameters trended toward the more severe disease presentation. RNA sequencing revealed several altered canonical pathways among the HCM vs WT groups including an increase in the EIF2 signaling, ILK signaling, actin nucleation by ARP-WASP complex, regulation of actin-based motility by Rho, VDR/RXR activation, and glutathione redox reactions pathways within the HCM mice. In contrast, the valine degradation, TCA Cycle II, Methionine Degradation, and Inositol Phosphate Compound pathways were notably down regulated in the HCM mice. Interestingly, seven of the genes that were differentially expressed in both the WT and HCM male vs female comparisons changed directions in fold change between the sexes. These data suggest a sexually-dimorphic HCM phenotype and identify several key pathways and genes that could be critical to sex differences seen in disease manifestation. NIH R01HL103840 and F31HL137408.