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.

BackgroundHigh-fat-diet (HFD) is associated with chronic low-grade inflammation. P2X7 purinergic receptors (P2X7R) are key regulators of inflammasome activation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether it regulates P2X7R expression to improve remodeling in cardiac myocytes treated by HFD is not completely clarified.MethodsThree groups of Sprague-Dawley (SD) rats were studied: (1) control group (fed a normal chow diet), (2) HFD group, and (3) HFD+ exercise group. H9c2 myocytes were pretreated with or without A438079 (a P2X7R inhibitor) and then exposed to 200 μM palmitic acid (PA) for 24 h. The levels of mRNA and protein were measured by real-time PCR and Western blot, respectively. Masson staining and hematoxylin-eosin (HE) staining were used to identify remodeling of the heart. The concentration of IL-1β in serum or supernatants were measured by ELISA.ResultsIn vivo, collagen deposition and the number of disordered cells significantly increased in the hearts of the HFD group compared to the control group. However, exercise markedly reversed these changes in the myocardium, and the same trends were observed in the expression of MMP9, collagen I and TGF-β. Notably, the expression of P2X7R, NLRP3, caspase-1 in the hearts, and serum IL-1β level were also greatly upregulated in the heart of the HFD diet rats, and all these changes were ameliorated in the HFD + EX group. As expected, exercise also reduced the number of TUNEL-positive cells, which was consistent with the caspase-3, Bax, and Bcl-2 results. Moreover, exercise reduced body weight and blood lipid concentrations in the HFD diet rats. In vitro, we observed that the hallmark of fibrosis, inflammation and apoptosis in H9c2 myocytes enhanced by PA, and the P2X7R inhibitor treatment significantly reduced the expression of the NLRP3, caspase-1, suppressed the secretion of IL-1β of H9c2 cells, inhibited collagen I, TGF-β, MMP9, Bax, caspase-3 levels and increased the expression of Bcl-2, compared with the PA group. In addition, a decrease of the number of TUNEL-positive cells used by A438079 further support that cardiomyocytes apoptosis could be inhibited.ConclusionAerobic exercise reversed the cardiac remodeling via the reduction of inflammation, fibrosis and apoptosis in HFD rats, at least in part through inhibiting P2X7R expression in cardiomyocytes.

Myocardial remodeling is one of the main lesions in the late stage of chronic heart failure and seriously affects the prognosis of patients. Continuous activation of the renin-angiotensin-aldosterone system (RAAS) contributes to the development of myocardial remodeling greatly, and angiotensin II (Ang II), its main constituent, can directly lead to cardiac remodeling through an inflammatory response and oxidative stress. Since Ang II-induced myocardial remodeling is closely related to inflammation, we tried to explore whether the anti-inflammatory drug oridonin (Ori) can reverse this process and its possible mechanism. Our study investigated that hypertrophy and fibrosis can be induced after being treated with Ang II in cardiomyocytes (H9c2 cells and primary rat cardiomyocytes) and C57BL/6J mice. The anti-inflammatory drug oridonin could effectively attenuate the degree of cardiac remodeling both in vivo and vitro by inhibiting GSDMD, a key protein of intracellular inflammation which can further activate kinds of inflammation factors such as IL-1β and IL-18. We illustrated that oridonin reversed cardiac remodeling by inhibiting the process of inflammatory signaling through GSDMD. After inhibiting the expression of GSDMD in cardiomyocytes by siRNA, it was found that Ang II-induced hypertrophy was attenuated. These results suggest that oridonin is proved to be a potential protective drug against GSDMD-mediated inflammation and myocardial remodeling.

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