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Sex differences in cardiac recovery and corresponding gene expression in a rat model of donation after circulatory death

ABSTRACT: Heart donation after circulatory death (DCD) can expand graft supply, but it exposes hearts to myocardial ischemia–reperfusion injury (IRI). Although sex differences in myocardial IRI are recognized, they remain underexplored in DCD. Therefore, we aimed to investigate whether sex differences induce changes in the expression of genes in response to cardiac DCD conditions, including IRI, which may contribute to sexual dimorphism in graft quality. Male, female, and ovariectomized (OVX) Wistar rat hearts underwent simulated DCD protocol with 0 or 22 minutes of warm ischemia, followed by oxygenated reperfusion under left-ventricular loading. Functional recovery was assessed and left-ventricular tissue analyzed by bulk RNA-sequencing. Warm ischemia reduced recovery in all sexes. Recovery of left ventricular function was significantly better in females than in males, with OVX resembling the males. Reperfusion induces inflammatory and hypoxia-responsive gene programs in all sexes. Overall, 136 genes correlated with recovery, many of which were more abundant in females, consistent with a role in improved post-ischemic function. Among these genes, Igfbp3, Fam78b, and Galnt10 were enriched in females compared to males and OVX, supporting a role for female sex hormones. Compared to male hearts, cardiac recovery is significantly higher in female hearts after exposure to DCD conditions and is accompanied by an increased expression of genes related to core homeostatic programs that have been connected to increased recovery. A significantly higher expression of genes related to energy metabolism, including fatty acid metabolism and inflammatory pathways, were more highly expressed in males compared to females and are associated with decreased recovery. This study identifies potential therapeutic targets underlying sex-specific differences in DCD heart recovery and highlights the importance of treating DCD hearts in a sexually dimorphic manner, considering differences in inflammatory pathways and metabolic adaptations, to improve cardiac graft quality in both sexes.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE317340 | GEO | 2026/05/26

REPOSITORIES: GEO

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Project description:Aims: We investigate sex differences and the role of oestrogen receptor beta (ERbeta) in a mouse model of pressure overload-induced myocardial hypertrophy. Methods and results: We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ER knockout (ERbeta-/-) C57Bl6 mice. All mice were characterised by echocardiography and haemodynamic measurements and were sacrificed nine weeks after surgery. Left ventricular (LV) samples were analysed by microarray profiling, real-time RT-PCR and histology. After nine weeks, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. These sex differences were abolished in ERbeta-/- mice. ERbeta deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that male WT hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than female hearts. ERbeta-/- mice exhibited a different transcriptome. Induction of pro-apoptotic genes after TAC occurred in ERbeta-/- mice of both sexes with a stronger expression in ERbeta-/- males. Histological analysis revealed, that cardiac fibrosis was more pronounced in male WT TAC than in female mice. This was abolished in ERbeta-/- mice. Apoptosis was significantly induced in both sexes of ERbeta-/- TAC mice, but it was most prominent in males. Conclusion: Female sex offers protection against ventricular chamber dilation in the TAC model. Both the female sex and ER attenuate the development of fibrosis and apoptosis; thus slowing the progression to heart failure. The influence of sex (male/female) and estrogen receptor beta expression (ERbeta knockout/wildtype) on cardiac hypertrophy (transverse aortic constriction/sham operated) was investigated. The left ventricular transcriptome of four individual mice for each combination of the three factors (sex, genotype, surgery) was detected with Affymetrix RAE 430 2.0 GeneChip arrays.

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Sex differences in cardiac recovery and corresponding gene expression in a rat model of donation after circulatory death

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