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Binge drinking exerts cardiac toxicity through various mechanisms, including oxidative stress and inflammation. NLRP3 inflammasomes possess both pro- and anti-inflammatory properties, although the role of NLRP3 in ethanol-induced cardiotoxicity remains unknown. This study is designed to examine the role of NLRP3 inflammasome in acute ethanol cardiotoxicity and the underlying mechanisms of action. Nine- to twelve-week-old adult male C57BL/6 mice are administered with ethanol (1.5 g/kg, twice daily, i.p.) for 3 days. A cohort of control and ethanol-challenged mice are treated with the NLRP3 inhibitor MCC950 (10 mg/kg/day, i.p., days 1 and 3). Myocardial geometry and function are monitored using echocardiography and cardiomyocyte edge-detection techniques. Levels of NLRP3 inflammasome, mitophagy and apoptosis are evaluated by western blot analysis and immunofluorescence techniques. Acute ethanol challenge results in abnormally higher cardiac systolic function, in conjunction with deteriorated cardiac diastolic function and cardiomyocyte contractile function. Levels of NLRP3 inflammasome and apoptosis are elevated, and mitophagy flux is blocked (elevated Pink1-Parkin and LC3B along with diminished p62 and Rab7) in mice receiving acute ethanol challenge. Although MCC950 does not elicit a notable effect on myocardial function, apoptosis or inflammasome activation in the absence of ethanol exposure, it effectively rescues acute ethanol cardiotoxicity, as manifested by restored myocardial and cardiomyocyte functional homeostasis, suppressed NLRP3 inflammasome activation and apoptosis, and improved mitophagy flux. Our data further suggest that FBXL2, an E3 ubiquitin ligase associated with mitochondrial homeostasis and mitophagy, is destabilized due to proteasomal degradation of caspase-1 by ethanol-induced hyperactivation of NLRP3-caspase-1 inflammasome signaling, resulting in mitochondrial injury and apoptosis. These findings denote a role for NLRP3 inflammasome in acute ethanol exposure-induced cardiotoxicity in an FBXL2-dependent manner and the therapeutic promise of targeting NLRP3 inflammasome for acute ethanol cardiotoxicity.

Early inflammatory responses post myocardial infarction (MI) is associated with increased myocardial fibrosis and cardiac remodelling. The NLRP3 inflammasome, a key factor in this response, regulates the expression of interleukins (IL)‐1β and IL‐18. Inhibiting the inflammatory process may be beneficial for post‐MI recovery. Bufalin effectively inhibits inflammation and fibrosis. The aim of this study was to evaluate the effects of bufalin and MCC950, an NLRP3 inflammasome inhibitor, as potential treatment agents for MI using an experimental mouse model. Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and subsequently treated with bufalin (0.5 mg/kg), MCC950 (10 mg/kg) or saline thrice a week for 2 weeks. After 4 weeks, cardiac function and myocardial fibrosis were evaluated. Myocardial levels of fibrotic markers and inflammatory factors were analysed using western blotting, enzyme‐linked immunosorbent assay, real‐time quantitative polymerase chain reaction and immunofluorescence. In mice with MI, cardiac ultrasonography showed decreased cardiac function and myocardial fibrosis. Bufalin treatment restored left ventricular ejection fraction and fractional shortening and decreased the myocardial infarct size. Moreover, both bufalin and MCC950 preserved cardiac function and relieved myocardial fibrosis, with no significant difference. Hence, the present study findings suggest that bufalin can alleviate fibrosis and improve cardiac function in a mouse model by suppressing NLRP3/IL‐1β signalling post‐MI. [ABSTRACT FROM AUTHOR]

Background: Aortic dissection (AD) is a life-threatening cardiovascular disorder with high mortality and lacking underlying mechanisms or effective treatments. REGγ, the 11S proteasome activator known to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner, emerges as a new regulator in the cardiovascular system.Methods: Using β-aminopropionitrile (BAPN)-subjected REGγ knockout AD mice and Ang II (angiotensin II)-treated REGγ deficiency vascular smooth muscle cells (VSMCs) to explore the effect of REGγ in AD progression.Results: REGγ was upregulated in mouse aorta of β-aminopropionitrile-induced AD model in vivo and Ang II-treated VSMCs in vitro. REGγ deficiency ameliorated AD progression in β-aminopropionitrile-induced mice by protecting against the switch in VSMCs from contractile to synthetic phenotype through suppressing RBM3 (RNA-binding motif protein 3) decay. Mechanically, REGγ interacted with and degraded the RNA-binding protein RBM3 directly, leading to decreased mRNA stability, lowered expression and transcriptional activity of transcription factor SRF (serum response factor), subsequently reduced transcription of VSMCs-specific contractile genes, α-SMA (alpha-smooth muscle actin) and SM22α (smooth muscle 22 alpha), caused the switch in VSMCs from contractile to synthetic phenotype and associated AD progression. Ablation of endogenous SRF or RBM3, or overexpressing exogenous RBM3 in VSMCs significantly blocked or reestablished the REGγ-dependent action on VSMCs phenotypic switch of Ang II stimulation in vitro. Furthermore, exogenously introducing RBM3 improved the switch in VSMCs from contractile to synthetic phenotype and associated AD features caused by REGγ in vivo.Conclusions: Our results demonstrated that REGγ promoted the switch in VSMCs from contractile to synthetic phenotype and AD progression by inhibiting RBM3-SRF pathway, indicated that modulating REGγ-proteasome activity may be a potential therapeutic approach for AD-associated cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]