Effect of landiolol on sex-related transcriptomic changes in the myocardium during sepsis

Abstract

Objectives The 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. Methods The 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. Results Our 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 Ca 2+ 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. Conclusion In 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. Electronic supplementary material The online version of this article (10.1186/s40635-019-0263-0) contains supplementary material, which is available to authorized users.

Female hormones prevent sepsis-induced cardiac dysfunction: an experimental randomized study

“…In the second part of our study, we looked for the underlying mechanism of changes in hemodynamic pro les. We previously identi ed, in a transcriptomic study, major differences in sepsis-induced deregulation of gene expression in male and female rats and con rmed the bene t of landiolol intake on cardiac function in male (13). Our current results highlight a similar gene expression pro le in OVR females to that found in males.…”

“…Total RNA was isolated from the left ventricles and qPCR experiments were performed as previously described (13). Statistical Analyses Data are expressed as means ± SEM.…”

Female hormones prevent sepsis-induced cardiac dysfunction: an experimental randomized study

“…In the second part of our study, we looked for the underlying mechanism of changes in hemodynamic profiles. We previously identified, in a transcriptomic study, major differences in sepsis-induced deregulation of gene expression in male and female rats and confirmed the benefit of landiolol intake on cardiac function in male 13 . Our current results highlight a similar gene expression profile in OVR females to that found in males.…”

“…Hearts, removed immediately after euthanasia, were dissected, frozen and stored at − 80 °C until analyses. Total RNA was isolated from the left ventricles and qPCR experiments were performed as previously described 13 . Primers used for trancripts detection are listed in Supplementary Table 1 .…”

Septic cardiomyopathy: Diagnosis and management

“… [117] Moreover, few studies have evaluated the impact of biological sex on SCM, [118] which has been shown to influence pathology and response to treatment in animal studies. [119] , [120] …”