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.
Background: Cardiac hypertrophy is initially an adaptive response of cardiomyocytes to neurohumoral or hemodynamic stimuli. Evidence indicates that Ang II (angiotensin II) or pressure overload causes GSDMD (gasdermin D) activation in cardiomyocytes and myocardial tissues. However, the direct impact of GSDMD on cardiac hypertrophy and its underlying mechanisms are not fully understood. Methods and Results: In this study, we examined the aberrant activation of GSDMD in mouse and human hypertrophic myocardia, and the results showed that GSDMD deficiency reduced Ang II or pressure overload–induced cardiac hypertrophy, dysfunction, and associated cardiomyocyte pyroptosis in mice. Mechanistically, Ang II–mediated GSDMD cleavage caused mitochondrial dysfunction upstream of STING (stimulator of interferon genes) activation in vivo and in vitro. Activation of STING, in turn, potentiated GSDMD-mediated cardiac hypertrophy. Moreover, deficiency of both GSDMD and STING suppressed cardiac hypertrophy in cardiac-specific GSDMD-overexpressing mice. Conclusions: Based on these findings, we propose a mechanism by which GSDMD generates a self-amplifying, positive feed-forward loop with the mitochondria-STING axis. This finding points to the prospects of GSDMD as a key therapeutic target for hypertrophy-associated heart diseases.
Cardiac hypertrophy is an adaptive cardiac response that accommodates the variable hemodynamic demands of the human body during extended periods of preload or afterload increase. In recent years, an increasing number of studies have pointed to a potential connection between myocardial hypertrophy and abnormal expression of non-coding RNAs. Circular RNA (circRNA), as one of the non-coding RNAs, plays an essential role in cardiac hypertrophy. However, few studies have systematically analyzed circRNA-related competing endogenous RNA (ceRNA) regulatory networks associated with cardiac hypertrophy. Therefore, we used public databases from online prediction websites to predict and screen differentially expressed mRNAs and miRNAs and ultimately obtained circRNAs related to cardiac hypertrophy. Based on this result, we went on to establish a circRNAs-related ceRNA regulatory network. This study is the first to establish a circRNA-mediated ceRNA regulatory network associated with myocardial hypertrophy. To verify the results of our analysis, we used PCR to verify the differentially expressed mRNAs and miRNAs in animal myocardial hypertrophy model samples. Our findings suggest that three mRNAs (Col12a1, Thbs1, and Tgfbr3), four miRNAs (miR-20a-5p, miR-27b-3p, miR-342-3p, and miR-378a-3p), and four related circRNAs (circ_0002702, circ_0110609, circ_0013751, and circ_0047959) may play a key role in cardiac hypertrophy.
Purpose: Schisandra is a well-known traditional Chinese medicine in East Asia. As a traditional Chinese medicine derivative with Schisandra chinensis as raw material, bicyclol is well known for its signi cant anti-in ammatory effect. Chronic in ammation plays an signi cant part in obesity-induced cardiomyopathy. Our purpose was to explore the effect and mechanism of bicyclol on obesity-induced cardiomyopathy.Methods: Mice fed with a high-fat diet (HFD) and cardiomyocytes stimulated by palmitic acid (PA) were used as models of obesity-related cardiomyopathy in vivo and in vitro, respectively. The therapeutic effect of bicyclol on pathological changes such as myocardial hypertrophy and brosis was evaluated by staining cardiac tissue sections. PCR was used to detect in ammatory factors in H9c2 cells and animal heart tissue after bicyclol treatment. Then, we used western blotting to detect the expression levels of myocardial hypertrophy related protein, myocardial brosis related protein, NF-κB and MAPK pathways.Results: Our results indicated that bicyclol treatment signi cantly alleviates HFD-induced myocardial in ammation, brosis and hypertrophy by inhibiting the MAPK and NF-κB pathways. Similar to animal level results, bicyclol could signi cantly inhibit PA-induced in ammation and prevent NF-κB and MAPK pathways to be activated. Conclusion: Our results showed that bicyclol is expected to become a potential drug to treat obesityinduced cardiomyopathy.
Pyroptosis serves a crucial function in various types of ischemia and reperfusion injuries. Oridonin, a tetracycline diterpene derived from Rabdosia rubescens, can significantly inhibit the aggregation of NLRP3-mediated inflammasome. This experiment is aimed at investigating the effect of oridonin on pyroptosis in mice cardiomyocytes. Based on the models of myocardial ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R), Evans Blue/TTC double staining, TUNEL staining, and Western blotting were applied to determine the effects of oridonin on myocardial damage, cellular activity and signaling pathways involved in pyroptosis. During I/R and H/R treatments, the extent of gasdermin D-N domains was upregulated in cardiomyocytes. Apart from that, oridonin improved cell survival in vitro and decreased the myocardial infarct size in vivo by also downregulating the activation of pyroptosis. Finally, the expression levels of ASC, NLRP3 and p-p65 were markedly upregulated in cardiomyocytes after H/R treatment, whereas oridonin suppressed the expression of these proteins. The present experiment revealed that myocardial I/R injury and pyroptosis can be alleviated and inhibited by oridonin pretreatment via NF-κB/NLRP3 signaling pathway, both in vivo and in vitro. Therefore, oridonin may serve as a potentially novel agent for the clinical treatment of myocardial ischemia-reperfusion injuries.
Background Acute myocardial infarction (AMI) is one of the leading contributors to morbidity and mortality worldwide, with a prevalence of nearly three million people, and more than one million deaths reported in the United States every year. Gasdermin D (GSDMD) is involved in the development of atherosclerosis as a key protein of proptosis. This study was designed to determine the potential relationship of GSDMD with AMI in Chinese patients. Methods One hundred patients with AMI and 50 controls were consecutively enrolled in this prospective observational study. GSDMD expression levels and other clinical variables in peripheral blood mononuclear cells (PBMCs) were measured upon admission to the hospital. All patients were followed up for 360 days, and the endpoint was considered the occurrence of major adverse cardiovascular events (MACE). Results GSDMD expression levels in the PBMCs of patients with AMI were significantly higher than those in the controls. Moreover, our analysis showed that GSDMD was an independent biomarker of AMI and had a promising diagnostic ability for it. Finally, the results suggested that high expression of GSDMD and diabetes increased the risk of MACE after AMI. Conclusions This study indicated that the GSDMD expression level in PBMCs was elevated in AMI patients and was closely associated with the pyroptosis of AMI.
To improve the operating efficiency of the bus transport system and service level to the public, the scheduling optimization of single-line bus route for express bus and shuttle bus was carried out during the rush hours. Based on the relevant basic assumptions, this paper established the parking judgment model and passenger ride selection model of express bus and shuttle bus. Meanwhile, taking passenger ride experience and bus company operating cost as the objective function, genetic algorithm was used to optimize the bus departure interval. In the optimization process, two schemes including discrete scheme and continuous scheme were provided. The models and optimization methods were applied to an actual single line bus route. The results show that, the discrete scheme has faster convergence speed and better optimization effect. The value of objective function decreases by 12.38%. Although the bus operation cost has increased slightly, considering the public commonweal of the bus transport system, the optimization results are still in line with the essence of its operation. The models and its optimization methods can provide a reference for the scheduling optimization of single-line bus route with the introduction of express bus and shuttle bus.
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