Ectopic accumulation of ceramide in cardiomyocytes modulates alcoholic cardiomyopathy via the TLR4‐dependent pathway. (11th April 2022)

• Record Type: Journal Article
• Authors: Wang, Cui; Li, Songtao; Liu, Qingsheng; Qian, Qianyu; Fu, Ai; Chen, Lin; Zhang, Lei; Suzaki, Toshinobu; Yu, ZhiLing; Dou, Xiaobing
• Is Part Of: Alcoholism. Volume 46:Number 6(2022)
• Page Start: 1011
• Page End: 1022
• Publication Date: 2022-04-11
• Subjects: alcoholic cardiomyopathy -- cell death -- ceramide -- TLR4; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.14822
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract: Background and aims: Excessive alcohol consumption predisposes drinkers to develop alcoholic cardiomyopathy. Although cardiomyocyte loss is the hallmark of cardiomyopathy, the underlying mechanism remains elusive. This study examined the potential mechanism of alcohol‐induced cardiomyocyte death in a mouse model of alcoholic cardiomyopathy. Methods: We established the alcoholic cardiomyopathy mouse model using C57BL/6J mice and confirmed it via echocardiography and histological examination. The cardiac ceramide content and profile were analyzed with a triple‐quadrupole mass spectrometer. The molecular mechanism underlying the accumulation of ceramide due to chronic alcohol consumption and ceramide‐induced cardiomyocyte death were investigated by in vivo and in vitro models. Finally, we established a TLR4 mutation model to explore the function of TLR4 in CH3/HeJ mice. Results: Cardiac lipotoxicity that followed alcohol exposure resulted mainly in C16:0‐, C18:0‐, and C24:1‐ceramide aggregation. Genes encoding the sphingosine hydrolysis enzymes (SMPD1 and SMPD2) rather than de novo synthetic biomarkers were markedly upregulated. Exogenous ceramide mimics (C6‐ceramide) werenderlying the accumulation of ceramide observed to cause H9C2 cardiomyocyte‐like cell death, which was consistent with results under palmate acid (PA) treatment. As a ceramide precursor, PA induces intracellular ceramide generation through TLR4 signaling, which can be abolished by an inhibitor of ceramide synthesis. Furthermore, mechanistic investigations demonstrated that pharmacological or genetic inhibition of TLR4 attenuated PA‐induced cell death and corresponding ceramide production. Moreover, global mutation of TLR4 in CH3/HeJ mice significantly reduced the accumulation of C24:0, C24:1, OH_C24:1, and total ceramide following alcohol challenge. Conclusions: Our findings demonstrate that ceramide accumulation plays a crucial role in alcoholic cardiomyopathy, effects that are partially mediated through the TLR4‐dependent pathway. Abstract : The present study clarified long‐chain ceramides augmentation in heart induced cardiomyocyte apoptosis in alcoholic cardiomyopathy mice model. Mechanistic investigation uncovered the elevated ceramides were mainly derived from sphingosine hydrolysis in a TLR4‐depedent pathway. Mutation of TLR4 reduced ceramides production and consequently ameliorated alcoholic cardiomyopathy. Data obtained in this study would provide a new insight into the pathology of alcoholic cardiomyopathy.