Empagliflozin alleviates the development of autoimmune myocarditis via inhibiting NF-κB-dependent cardiomyocyte pyroptosis.

Autoimmune myocarditis, which falls within the broad spectrum of myocarditis, is characterized by an excessive inflammatory response in the heart, and can progress into dilated cardiomyopathy and irreversible heart failure in all possibility. However, effective clinical therapeutics are limited due to its complex inflammatory reactions. Empagliflozin (EMPA) has been previously demonstrated to possess anti-inflammatory properties. This study aimed to determine the improvement effects of EMPA on cardiac dysfunction under the condition of autoimmune myocarditis, and to further investigate the potential mechanisms. In vivo, all male Balb/c mice were randomly divided into four groups: control, experimental autoimmune myocarditis (EAM), EAM+EMPA and EMPA. In vitro, the effects of EMPA on IL-18-stimulated H9C2 cells were explored and the underlying molecular mechanisms were further determined. EMPA treatment significantly inhibited the development of autoimmune myocarditis, and mice treated with EMPA exhibited improved cardiac function compared with that in the EAM group, potentially through modulating pyroptosis of myocardium. Specifically, the NF-κB pathway was activated in the hearts of the EAM mice, which further activated NLRP3 inflammasome-dependent pyroptosis. EMPA treatment significantly inhibited such activation, thus alleviating inflammatory reactions in the context of EAM. Moreover, in vitro, we also observed that EMPA significantly inhibited pyroptosis of IL-18-stimulated H9C2 cells, and reduced nuclear translocation of NF-κB and degradation of activated IκBα. This work provides the first direct evidence that EMPA can inhibit myocardial inflammation and improve cardiac function in EAM mice, partly attributed to the drug-induced suppression of cardiomyocyte pyroptosis via disrupting the NF-κB pathway.

Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT/MAPK/NF-κB Pathway.

Sepsis is a dysregulated systemic inflammatory response that often leads to cardiac dysfunction, which is termed sepsis-induced cardiomyopathy (SIC). Harmine, a natural ß-carboline alkaloid compound, has been shown to exert pharmacological effects on several diseases. Here, we investigated whether harmine protected against SIC development and the underlying mechanisms. In vitro, the expression of the M1 phenotype markers iNOS and COX-2 was increased in RAW 264.7 cells stimulated with lipopolysaccharide (LPS), but this effect was reversed by the harmine intervention. Furthermore, LPS-induced increases in the levels of inflammatory cytokines, including IL-1ß, IL-6, TNF-α, iNOS, COX-2, PGE2 and TXB2, generated by macrophages were suppressed when the cells were pretreated with harmine. Meanwhile, our findings showed that harmine administration effectively attenuated inflammation and apoptosis in H9c2 cells in the proinflammatory environment produced by macrophages, as evidenced by reductions in NLRP3 and cleaved caspase 3 levels and the p-NF-κB/NF-κB ratio. The western blot results indicated that the mechanisms underlying harmine-mediated inhibition of M1 polarization might be associated with suppression of STAT1/3, NF-κB and MAPK activation. Furthermore, an LPS injection induced cardiac dysfunction and decreased the survival rate of mice, which were alleviated by harmine treatment, and the relevant mechanism was possibly attributed to a drug-induced attenuation of the inflammatory and apoptotic processes in cardiomyocytes. Collectively, these results implied that harmine treatment protected against SIC by suppressing M1 phenotypic polarization and inflammation in macrophages.