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. 2023 Oct;39(5):2365-2379.
doi: 10.1007/s10565-022-09727-z. Epub 2022 Jun 28.

Knockdown of HDAC6 alleviates ventricular remodeling in experimental dilated cardiomyopathy via inhibition of NLRP3 inflammasome activation and promotion of cardiomyocyte autophagy

Xuefeng Pang  1 , Qigang Guan  1 , Xue Lin  2 , Ning Chang  3
Affiliations

Knockdown of HDAC6 alleviates ventricular remodeling in experimental dilated cardiomyopathy via inhibition of NLRP3 inflammasome activation and promotion of cardiomyocyte autophagy

Xuefeng Pang et al. Cell Biol Toxicol. 2023 Oct.

Abstract

Histone deacetylases (HDACs) has been implicated in cardiac diseases, while the role of HDAC6 in dilated cardiomyopathy (DCM) remains obscure. The in silico analyses predicted potential association of HDAC6 with autophagy-related genes and DCM. Thus, we evaluated the functional relevance of HDAC6 in DCM in vivo and in vitro. We developed a rat model in vivo and a cell model in vitro by doxorubicin (DOX) induction to simulate DCM. HDAC6 expression was determined in myocardial tissues of DCM rats. DCM rats exhibited elevated HDAC6 mRNA and protein expression as compared to sham-operated rats. We knocked HDAC6 down and/or overexpressed NLRP3 in vivo and in vitro to characterize their roles in cardiomyocyte autophagy. It was established that shRNA-mediated HDAC6 silencing augmented cardiomyocyte autophagy and suppressed NLRP3 inflammasome activation, thus ameliorating cardiac injury in myocardial tissues of DCM rats. Besides, in DOX-injured cardiomyocytes, HDAC6 silencing also diminished NLRP3 inflammasome activation and cell apoptosis but enhanced cell autophagy, whereas ectopic NLRP3 expression negated the effects of HDAC6 silencing. Since HDAC6 knockdown correlates with enhanced cardiomyocyte autophagy and suppressed NLRP3 inflammasome activation through an interplay with NLRP3, it is expected to be a potential biomarker and therapeutic target for DCM. 1. HDAC6 was up-regulated in DCM rats. 2. HDAC6 knockdown promoted cardiomyocyte autophagy to relieve cardiac dysfunction. 3. HDAC6 knockdown inhibited NLRP3 inflammasome and promoted cardiomyocyte autophagy. 4. Silencing HDAC6 promoted autophagy and repressed apoptosis in cardiomyocytes. 5. This study provides novel therapeutic targets for DCM.

Keywords: Autophagy; Cardiomyocytes; Dilated cardiomyopathy; Histone deacetylase 6; Inflammasome; Myocardial injury; NLRP3; Ventricular remodeling.

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References

    1. Biasizzo M, Kopitar-Jerala N. Interplay between NLRP3 inflammasome and autophagy. Front Immunol. 2020;11:591803. https://doi.org/10.3389/fimmu.2020.591803
    1. Bielecka-Dabrowa A, Mikhailidis DP, Hannam S, Aronow WS, Rysz J, Banach M. Statins and dilated cardiomyopathy: do we have enough data? Expert Opin Investig Drugs. 2011;20(3):315–23. - DOI - PubMed
    1. Cao Z, Wang Y, Long Z, He G. Interaction between autophagy and the NLRP3 inflammasome. Acta Biochim Biophys Sin (shanghai). 2019;51(11):1087–95. - DOI - PubMed
    1. Cao Z, Gu Z, Lin S, Chen D, Wang J, Zhao Y, et al. Attenuation of NLRP3 inflammasome activation by indirubin-derived PROTAC targeting HDAC6. ACS Chem Biol. 2021;16(12):2746–51. - DOI - PubMed
    1. Caragnano A, Aleksova A, Bulfoni M, Cervellin C, Rolle IG, Veneziano C, et al. Autophagy and inflammasome activation in dilated cardiomyopathy. J Clin Med. 2019;8(10):1519. https://doi.org/10.3390/jcm8101519

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