Abstract
Myocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and the underlying mechanism. C57BL/6 wild-type (WT) mice and age-matched Gsdmd-knockout (Gsdmd -/-) mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg) to mimic sepsis. The results showed that GSDMD-NT, the functional fragment of GSDMD, was upregulated in the heart tissue of septic WT mice induced by LPS, which was accompanied by decreased cardiac function and myocardial injury, as shown by decreased ejection fraction (EF) and fractional shortening (FS) and increased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB), and lactate dehydrogenase (LDH). Gsdmd -/- mice exhibited protection against LPS-induced myocardial dysfunction and had a higher survival rate. Gsdmd deficiency attenuated LPS-induced myocardial injury and cell death. Gsdmd deficiency prevented LPS-induced the increase of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum, as well as IL-1β and TNF-α mRNA levels in myocardium. In addition, LPS-mediated inflammatory cell infiltration into the myocardium was ameliorated and activation of NF-κB signaling pathway and the NOD-like receptor protein 3 (NLPR3) inflammasome were suppressed in Gsdmd -/- mice. Further research showed that in the myocardium of LPS-induced septic mice, GSDMD-NT enrichment in mitochondria led to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which further regulated the activation of the NLRP3 inflammasome. In summary, our data suggest that GSDMD plays a vital role in the pathophysiology of LPS-induced myocardial dysfunction and may be a crucial target for the prevention and treatment of sepsis-induced myocardial dysfunction.
Highlights
Myocardial dysfunction is a serious complication of sepsis
These findings indicate that Gasdermin D (GSDMD) plays a role in septic myocardial dysfunction induced by LPS
The results showed that the protein expressions of NOD-like receptor protein 3 (NLRP3) and cleaved caspase-1, as well as the IL-1β concentration in the supernatant, were decreased in H9c2 cardiomyocytes transfected with si-Gsdmd after treatment with LPS and nigericin (Figures 5H,I), which was consistent with the results of animal experiments
Summary
Myocardial dysfunction is a serious complication of sepsis. It has been reported that 20–60% of patients with sepsis develop myocardial dysfunction (Charpentier et al, 2004; VieillardBaron et al, 2008). Multiple mechanisms are thought to be participated in the pathogenesis of myocardial dysfunction in sepsis, including persistent inflammatory response, mitochondrial dysfunction, oxidative stress injury, autonomic nervous system dysregulation, and apoptosis (Cimolai et al, 2015; Essandoh et al, 2015; Neri et al, 2016). Tumor necrosis factorα (TNF-α) and Interleukin-1β (IL-1β) are primary players in the hierarchy of proinflammatory mediator cascades (Loppnow et al, 1998) These inflammatory cytokines disturb energy metabolism, destroy β-adrenergic signaling, stimulate excess production of nitric oxide, and imbalance calcium homeostasis, leading to myocardial dysfunction (Zhong et al, 1997; Rudiger & Singer, 2007; Alves-Filho et al, 2008; de Montmollin et al, 2009; Smeding et al, 2012; Drosatos et al, 2015)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
