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

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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.

Graphical abstract

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.

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Data availability

The datasets generated and/or analyzed during the current study are available in the manuscript and supplementary materials.

Abbreviations

DCM:

Dilated cardiomyopathy

HDACs:

Histone deacetylases

GO:

Gene ontology

DOX:

Doxorubicin

NC:

Negative control

HE:

Hematoxylin-eosin

TEM:

Transmission electron microscope

PVDF:

Polyvinylidene fluoride

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, the First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China

    Xuefeng Pang & Qigang Guan

  2. Department of Cardiovascular Medicine, Peking Union Medical College Hospital, Beijing, 100730, People’s Republic of China

    Xue Lin

  3. Department of Digestive Diseases, the First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001, People’s Republic of China

    Ning Chang

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  1. Xuefeng Pang
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  2. Qigang Guan
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Contributions

Xuefeng Pang designed the study. Qigang Guan and Ning Chang collated the data, carried out data analyses, and produced the initial draft of the manuscript. Xue Lin contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Ning Chang.

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Experiments were approved by the Animal Care and Use Committee of the First Hospital of China Medical University, in accordance with Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

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The authors declare no competing interests.

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Pang, X., Guan, Q., Lin, X. et al. Knockdown of HDAC6 alleviates ventricular remodeling in experimental dilated cardiomyopathy via inhibition of NLRP3 inflammasome activation and promotion of cardiomyocyte autophagy. Cell Biol Toxicol 39, 2365–2379 (2023). https://doi.org/10.1007/s10565-022-09727-z

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