Gender dimorphism of the cardiac dysfunction in murine sepsis: signalling mechanisms and age-dependency.

Jianmin Chen,Massimo Collino,Nimesh S A Patel,Sina M Coldewey,Christoph Thiemermann,Fausto Chiazza,Carmen Infante-Duarte

doi:10.1371/journal.pone.0100631

Abstract

Development of cardiac dysfunction is associated with increased morbidity and mortality in patients with sepsis. Increasing evidence shows that gender determines the degree of inflammatory response of the host and that females tolerate sepsis better than males. It is unknown whether gender affects the cardiac dysfunction in animals or patients with sepsis. To investigate this, male or female C57BL/6 mice were subjected to either lipopolysaccharide (LPS)/peptidoglycan (PepG) co-administration or cecal ligation and puncture (CLP). At 18 hours after LPS/PepG injection or 24 hours after CLP, cardiac function was evaluated by echocardiography. The septic insult caused a significant cardiac dysfunction in both genders. However, the cardiac dysfunction was significantly less pronounced in females in comparison with males subjected to LPS (3 mg/kg)/PepG (0.1 mg/kg) or CLP. Compared with males injected with LPS (3 mg/kg)/PepG (0.1 mg/kg), western blotting analysis of the myocardium from females injected with LPS/PepG revealed i) profound increases in phosphorylation of Akt and eNOS; ii) significant decreases in phosphorylation of IκBα, nuclear translocation of the NF-κB subunit p65, decreased expression of iNOS and decreased synthesis of TNF-α and IL-6 in the heart. However, the gender dimorphism of the cardiac dysfunction secondary to LPS/PepG was not observed when higher doses of LPS (9 mg/kg)/PepG (1 mg/kg) were used. In conclusion, the cardiac dysfunction caused by sepsis was less pronounced in female than in male mice. The protection of female hearts against the dysfunction associated with sepsis is (at least in part) attributable to cardiac activation of the Akt/eNOS survival pathway, decreased activation of NF-κB, and decreased expression of iNOS, TNF-α and IL-6. It should be noted that the observed gender dimorphism of the cardiac dysfunction in sepsis was not seen when a very severe stimulus (high dose of LPS/PepG co-administration) was used to cause cardiac dysfunction.

Highlights

Sepsis is one of the most common causes of morbidity and mortality among admissions to the intensive care unit [1,2]
Female mice subjected to LPS/PepG exhibited significantly higher EF, fractional shortening (FS) and fractional area change (FAC) in comparison with male mice (P,0.05; Figure 1A–D), indicating the cardiac dysfunction caused by LPS/PepG was less pronounced in female than in male animals
To obtain a better insight into the mechanisms underlying the observed gender dimorphism of the cardiac response to sepsis, we investigated the phosphorylation of Akt, endothelial nitric oxide synthase (eNOS) and IkBa, nuclear translocation of nuclear factor (NF)-kB subunit p65, inducible nitric oxide synthase (iNOS) expression, as well as tumor necrosis factor (TNF)-a and IL-6 expression in murine hearts; When compared to the hearts of male mice subjected to LPS/PepG, hearts of female mice subjected to LPS/PepG showed i) profound increases in phosphorylation of Akt and eNOS; ii) reductions in phosphorylation of IkBa and nuclear translocation of the NF-kB subunit p65, iii) reduced expression of the pro-inflammatory cytokines TNF-a and IL-6, and iv) reduced expression of iNOS

Summary

Introduction

Sepsis is one of the most common causes of morbidity and mortality among admissions to the intensive care unit [1,2]. In a number of clinical and epidemiological studies, a significantly increased survival rate was reported in female patients when compared with male patients with sepsis [6,7,8,9]. This may be associated with lower pro-inflammatory and higher anti-inflammatory cytokine levels in female patients [9]. Further basic research studies confirmed these clinical data on gender dimorphism following sepsis These experimental studies suggested that females had immunologic advantage and showed a significantly increased survival rate compared with males following induction of polymicrobial sepsis by cecal ligation and puncture (CLP) [12]. Estrogen treatment attenuated the liver dysfunction and intestine injury caused by sepsis in rats with decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and ameliorated oxidative organ damage [13], while testosterone receptor blockade with flutamide following trauma-hemorrhage restored immune depression and significantly decreased the mortality after a subsequent septic challenge in male animals [14]

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