Abstract
ObjectivesThe aims of this study are to better understand phenotypic differences between male and female rats during sepsis, to characterise the contribution of the beta1-adrenergic blocker landiolol to septic cardiomyopathy and to determine why landiolol induces divergent effects in males and females.MethodsThe myocardial transcriptional profiles in male and female Wistar rats were assessed after the induction of sepsis by cecal ligation and puncture and addition of landiolol.ResultsOur results showed major differences in the biological processes activated during sepsis in male and female rats. In particular, a significant decrease in processes related to cell organisation, contractile function, ionic transport and phosphoinositide-3-kinase/AKT (PI3K/AKT) signalling was observed only in males. The transcript of ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3 (SERCA3) was sex-differently regulated. In males, landiolol reversed several signalling pathways dysregulated during sepsis. The expression level of genes encoding tubulin alpha 8 (TUBA8) and myosin heavy chain 7B (MYH7) contractile proteins, phosphatase 2 catalytic subunit alpha (PPP2CA), G protein-coupled receptor kinase 5 (GRK5) and A-kinase anchoring protein 6 (AKAP6) returned to their basal levels. In contrast, in females, landiolol had limited effects.ConclusionIn males, landiolol reversed the expression of many genes that were deregulated in sepsis. Conversely, sepsis-induced deregulation of gene expression was less pronounced in females than in males, and was maintained in the landiolol-treated females. These findings highlight important sex-related differences and confirm previous observations on the important benefit of landiolol intake on cardiac function in male rats.
Highlights
The pathophysiology of sepsis involves a complex mix of systemic factors and molecular, metabolic and structural changes in cardiomyocytes [1]
These results support our previous findings obtained by Magnetic resonance imaging (MRI) studies, showing decreased indexed stroke volume (SVi), cardiac index (CI) and indexed end-diastolic volume (EDVi) after cecal ligation and puncture (CLP) in males, whereas only CI and End-diastolic volume index (EDVi) decreased in females
We found common functional annotations induced by sepsis in both sexes, but many processes associated with the development, differentiation, organisation and function of cardiac muscle cells were deregulated only in males
Summary
The pathophysiology of sepsis involves a complex mix of systemic factors and molecular, metabolic and structural changes in cardiomyocytes [1]. These include the presence of circulating depressant factors, such as endotoxin and nitric oxide [2], pro-inflammatory cytokines [3], myocyte cell death, abnormal cardiac energetics [4, 5], alterations in adrenergic signalling and intra-cellular calcium cycling, impaired electromechanical coupling and mitochondrial dysfunction [6]. In experimental models of sepsis, a selective β1-blocker efficiently improved both cardiac and vascular functions and down-regulated inflammatory pathways [12,13,14,15,16]. To our knowledge, no large-scale studies have been conducted on the effect of a selective β1-blocker in experimental models of sepsis
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