<p>Emodin alleviates myocardial ischemia/reperfusion injury by inhibiting gasdermin D-mediated pyroptosis in cardiomyocytes</p>

Abstract

Background Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury. Pyroptosis is a proinflammatory programmed cell death that is related to many diseases. The present study investigated the effect of emodin on pyroptosis in cardiomyocytes. Materials and methods Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups. I/R model was subjected to 30 minutes’ ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion. Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours. The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA. Results The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment. Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis. Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins. Conclusion This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro. The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, emodin may provide an alternative treatment for myocardial I/R injury.

Molecular Mechanisms of Action of Emodin: As an Anti-Cardiovascular Disease Drug

“…Emodin treatment in H9c2 cells with myocarditis Anti-apoptosis (Liu et al, 2013) caspase-3↓, Bcl-2↑ Emodin treatment in BALB/c mice and HEp-2 cells with viral myocarditis (Zhang et al, 2019) miR-138↑, MLK3↓, p53 and p21↓, cyclin D1↑, caspase-3 and caspase-9↓Sirt1/AKT, and Wnt/b-catenin pathways activated, Emodin treatment in H9c2 cells with myocardial ischemia (Huang et al, 2019) miR-26a↓, survivin↑, caspase-3, and caspase-9↓, JAK1/STAT3 signal activated Emodin treatment in H9c2 cells with myocardial ischemia (Ye et al, 2019) GSDMD-N↓, IL-1b↓, TLR4/MyD88/NF-kB/NLRP3 inhibited Emodin treatment in Sprague-Dawley rats cardiomyocytes with ischemia/reperfusion injury Anti-myocardial fibrosis (Xiao et al, 2019) MTA3↑, COL1A2, and a-SMA↓ Emodin treatment in mouse model of pathological cardiac hypertrophy with excess fibrosis Anti-cardiac hypertrophy (Evans et al, 2020) I HDAC and II HDAC activity inhibited, histone acetylation in cardiomyocytes↑, ERK phosphorylation inhibited Emodin treatment in C57BL/6 mice with cardiac hypertrophy (transverse aortic constriction-induced) and fibrosis (AngII-induced) (Gao et al, 2020) SIRT3↑, modulation of mitochondrial SIRT3 and its downstream signaling pathway…”

“…Therefore, GSDMD-N is the executioner of pyroptotic cell death. It has been reported that I-R injury could activate pyroptosis, which were at least partially mediated by the TLR4/MyD88/NF-kB/NLRP3 inflammasome pathway by Ye et al (2019). Emodin (10 µM) inhibits the expression of TLR4 by decreasing ROS production and reduces the expression of GSDMD-N by decreasing the expression of TLR4, MyD88, NF-kB, and the NLRP3 inflammasome.…”

N-acetylcysteine alleviates post-resuscitation myocardial dysfunction and improves survival outcomes via partly inhibiting NLRP3 inflammasome induced-pyroptosis

“…The NLR3 inflammasome complex including NLRP3, ASC and pro-caspase-1, cleaves and activates caspase-1, then caspase-1 cleaves GSDMD, the later initiates pyroptosis and controls the release of proinflammatory cytokines [ 28 , 29 ]. In previous study, it has been demonstrated that local myocardial I/R injury can induce increased expression of NLRP3 inflammasome in myocardial tissues [ 30 ]. In this study, we established a cardiac arrest model and detected NLRP3 inflammasome and GSDMD in myocardial tissues after global myocardial I/R injury.…”

MiR-149 Aggravates Pyroptosis in Myocardial Ischemia-Reperfusion Damage via Silencing FoxO3

“…Currently, increasing evident indicated that pyroptosis, morphologically characterized by inflammatory related intracellular programmed death, might be involved in cardiac 1/R injury [32], for example, Ye et al highlighted that inhibition of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway mediated pyroptosis could alleviate myocardial I/R injury in both cellular and animal models [33]. The causes of pyroptosis in I/R damage progression considered that I/R might offer a combination of priming and triggering which subsequently activated the inflammasome pathway [34].…”

“…The causes of pyroptosis in I/R damage progression considered that I/R might offer a combination of priming and triggering which subsequently activated the inflammasome pathway [34]. Indeed, the expression of pyroptotic indicator as NLRP3 was found to be remarkable increased after reperfusion resulting in cell death, a process which contributed to activate caspase-1 in response to endogenous and exogenous danger signals, leading to product and maturate pro-inflammatory cytokines IL-1β and IL-18 during innate immunity process [33]. Meanwhile, it has been shown that caspase-1 could form pores in the cytomembrane, allowing water to enter the cell, causing cell swelling and eventual lysis [32].…”