A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

Abstract

BackgroundHeart failure preceded by hypertrophy is a leading cause of death, and sex differences in hypertrophy are well known, although the basis for these sex differences is poorly understood.Methods and ResultsThis study used a systems biology approach to investigate mechanisms underlying sex differences in cardiac hypertrophy. Male and female mice were treated for 2 and 3 weeks with angiotensin II to induce hypertrophy. Sex differences in cardiac hypertrophy were apparent after 3 weeks of treatment. RNA sequencing was performed on hearts, and sex differences in mRNA expression at baseline and following hypertrophy were observed, as well as within‐sex differences between baseline and hypertrophy. Sex differences in mRNA were substantial at baseline and reduced somewhat with hypertrophy, as the mRNA differences induced by hypertrophy tended to overwhelm the sex differences. We performed an integrative analysis to identify mRNA networks that were differentially regulated in the 2 sexes by hypertrophy and obtained a network centered on PPARα (peroxisome proliferator‐activated receptor α). Mouse experiments further showed that acute inhibition of PPARα blocked sex differences in the development of hypertrophy.ConclusionsThe data in this study suggest that PPARα is involved in the sex‐dimorphic regulation of cardiac hypertrophy.

Neutrophils in Post-myocardial Infarction Inflammation: Damage vs. Resolution?

“…Maladaptive remodeling following MI encompasses three prominent closely linked and co-dependent progressive processes: hypertrophy, inflammation and fibrosis. Human data from hypertrophied (non-ischemic) patients, experimental hypertrophy models and recent systems biology approaches revealed gender-specific alterations in LV hypertrophy, pro-inflammatory and pro-fibrotic gene expression and collagen deposition ( 72 – 74 ). These findings combined with conflicting observations regarding the effects of steroids on risk for or outcome post-MI imply the necessity to further elicit gender-differences in the type and extent of the different remodeling sub-processes.…”

PathwayPCA: an R/Bioconductor Package for Pathway Based Integrative Analysis of Multi‐Omics Data

“…[ 26 ] A recent integrative systems biology study showed that the miRNA‐mRNA network also plays an important role for gender differences in cardiac hypertrophy. [ 27 ] The genes with large PC loadings in this identified pathway include PPP3R1 , STAT3 , and TGFB1 , which regulate miRNA hsa‐mir‐133b, hsa‐mir‐21, and MIR29A. In Figure , we grouped subjects by median PC1 values for each sex.…”

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy

“…However, transcriptomic analysis has yet to be analyzed in a sex‐specific manner, let alone in a TNNC1 model (Green et al, 2016; Vakrou et al, 2018). A previous study utilizing a systems biology approach investigating the sex differences in mice after angiotensin II‐induced hypertrophy found that inhibition of PPARα by a PPARα inhibitor blocked the sex differences in the development of cardiac hypertrophy (Harrington et al, 2017). Below we discuss some key findings for the transcriptomic analysis of our HCM mouse model that may explain the sexual dimorphic phenotype observed in the echocardiography.…”

“…However, based on our physiological results in mice of different sexes, we wanted to determine whether some effects of a specific mutation in cTnC that cause HCM may actually be exacerbated in women. Several RNA‐sequencing based studies implicate genetic modifiers (Christodoulou et al, 2014) or mRNA networks that may play a role in disease expression between the sexes (Harrington et al, 2017). Gaining a better understanding of how this dimorphism is altered in cardiomyopathies of differing etiologies may provide evidence of specific networks of genes that are impacted.…”