GSDMD contributes to myocardial reperfusion injury by regulating pyroptosis

Abstract

BackgroundGasdermin D (GSDMD) plays an essential role in the pathway of pyroptosis. However, whether GSDMD participates in myocardial ischaemia/reperfusion injury (MI/RI) remains poorly understood.MethodsSerum levels of GSDMD and IL-18 in ST-segment elevation myocardial infarction (STEMI) patients were measured by ELISA. The expression of GSDMD and GSDMD N-terminal (GSDMD-NT) in vivo and in vitro was assessed by western blot and immunofluorescence staining. GSDMD-/- mice and wild type (WT) mice were induced MI/RI, followed by cardiac ultrasound and histological analysis.ResultsClinically, patients suffering from STEMI after percutaneous coronary intervention (PCI) exhibited higher levels of GSDMD and IL-18 than that in the controls. In vitro, the cleavage of GSDMD was significantly upregulated in macrophages exposed to hypoxia/reoxygenation or H2O2. In vivo, the levels of GSDMD and GSDMD-NT increased notably after MI/RI, especially in macrophages infiltrating in the infarct area. Moreover, compared with WT mice, GSDMD-/- mice showed reduced infarct size (25.45 ± 3.07% versus 36.47 ± 3.72%), improved left ventricular ejection fraction (37.71 ± 1.81% versus 29.44 ± 2.28%) and left ventricular fractional shortening (18.01 ± 0.97% versus 13.62 ± 1.15%) as well as attenuated pathological damage after I/R injury, along with reduced levels of proinflammatory cytokines and decreased infiltration of neutrophils.ConclusionsOur study revealed that GSDMD deficiency significantly alleviated the inflammatory response by regulating pyroptosis, reduced the infarct size and preserved cardiac function after MI/RI, thus providing a potential strategy for the treatment of myocardial reperfusion injury.

Knocking down GALNT6 promotes pyroptosis of pancreatic ductal adenocarcinoma cells through NF-κB/NLRP3/GSDMD and GSDME signaling pathway

“…Our results showed that knockdown of GALNT6 significantly increased the expression of inflammatory cytokines IL-1b, IL-18, IL-6 and TNF-a in PDAC cells. In additionally, GSDMD, the executor of pyroptosis, can be cleave by activated caspase-1 to generate GSDMD-N, which perforates the cell membrane and releases the IL-1b, IL-18, and other pro-inflammatory cytokines into the extracellular matrix (42). Here, we found that knockdown of GALNT6 significantly increased the expression of GSDMD in PDAC cells.…”

A seven-immune-genes risk model predicts the survival and suitable treatments for patients with skin cutaneous melanoma

“…Our ICrisk signature has integrated 7 IRGs (ARNTL, GSDMD, HAPLN3, IRX3, N4BP2L1, NUB1, PARP11). A subset of these identified genes are not solely defined to be associated with carcinogenesis but rather to play a regulatory role in non-malignant physiological or pathological processes, such as ARNTL controlling circadian rhythms [ 20 ], GSDMD regulating inflammatory responses in cardiac and lung injury pyroptosis [ 21 , 22 ], and IRX3 regulating obesity-related metabolism [ 23 ]. In recent years, studies have started supporting their roles in cancer pathology ( Table 2 ).…”

Perfect duet: Dual recombinases improve genetic resolution

“…In order to obtain functional information at the cellular level, typically genes associated with cell death, pyroptosis, or apoptosis are endogenously expressed. For instance, GSDMD N‐terminal (GSDMD‐NT) could induce pyroptosis, 78,79 and P21 induces cell proliferation inhibition and senescence 80,81 . Besides, chemical‐genetic cell ablation strategies such as the NTR‐MTZ system in zebrafish, and the DT‐DTR system in mammals also work efficiently under spatial and temporal control 82,83 …”