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GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation
Shanshan Dai1, Bozhi Ye2, Lingfeng Zhong2
1The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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.
Insights
Gasdermin D (GSDMD) fragment GSDMD-NT contributes to sepsis-induced myocardial dysfunction by damaging mitochondria. Blocking GSDMD protects cardiac function and improves survival in septic mice.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Sepsis-induced myocardial dysfunction is a major cause of mortality.
- The precise molecular mechanisms underlying sepsis-induced cardiac dysfunction remain incompletely understood.
- Gasdermin D (GSDMD) has emerged as a key mediator of inflammatory cell death.
Purpose of the Study:
- To investigate the role of GSDMD in the development of cardiac dysfunction during sepsis.
- To elucidate the molecular mechanisms by which GSDMD contributes to myocardial injury in sepsis.
- To evaluate GSDMD as a potential therapeutic target for sepsis-induced myocardial dysfunction.
Main Methods:
- Lipopolysaccharide (LPS) was used to induce sepsis in wild-type (WT) and GSDMD-knockout (Gsdmd-/-) C57BL/6 mice.
- Cardiac function was assessed by measuring ejection fraction (EF) and fractional shortening (FS).
- Myocardial injury markers (cTnI, CK-MB, LDH), inflammatory cytokines (IL-1β, TNF-α), mitochondrial function, reactive oxygen species (ROS) production, and NF-κB/NLRP3 inflammasome activation were analyzed.
Main Results:
- LPS-induced sepsis led to increased GSDMD-NT in cardiac tissue, decreased cardiac function, and elevated myocardial injury markers in WT mice.
- Gsdmd-/- mice showed protection against LPS-induced cardiac dysfunction, reduced myocardial injury, and improved survival rates.
- GSDMD deficiency attenuated inflammatory responses, suppressed NF-κB and NLRP3 inflammasome activation, and prevented mitochondrial dysfunction and ROS overproduction in the myocardium.
Conclusions:
- GSDMD plays a critical role in the pathogenesis of sepsis-induced myocardial dysfunction.
- GSDMD-NT contributes to cardiac injury by inducing mitochondrial dysfunction and ROS production, thereby activating the NLRP3 inflammasome.
- Targeting GSDMD may represent a promising therapeutic strategy for managing sepsis-induced myocardial dysfunction.
