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.

中文翻译：

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HDAC6 的敲低通过抑制 NLRP3 炎性体激活和促进​​心肌细胞自噬减轻实验性扩张型心肌病的心室重塑

组蛋白脱乙酰酶 (HDAC) 与心脏病有关，而 HDAC6 在扩张型心肌病 (DCM) 中的作用仍不清楚。计算机分析预测了 HDAC6 与自噬相关基因和 DCM 的潜在关联。因此，我们在体内和体外评估了 HDAC6 在 DCM 中的功能相关性。我们通过阿霉素 (DOX) 诱导建立了体内大鼠模型和体外细胞模型来模拟 DCM。测定 DCM 大鼠心肌组织中的 HDAC6 表达。与假手术大鼠相比，DCM 大鼠表现出 HDAC6 mRNA 和蛋白表达升高。我们在体内和体外敲低 HDAC6 和/或过表达 NLRP3，以表征它们在心肌细胞自噬中的作用。研究表明，shRNA 介导的 HDAC6 沉默可增强心肌细胞自噬并抑制 NLRP3 炎性体激活，从而改善 DCM 大鼠心肌组织的心脏损伤。此外，在DOX损伤的心肌细胞中，HDAC6沉默还减少了NLRP3炎性体激活和细胞凋亡，但增强了细胞自噬，而异位NLRP3表达抵消了HDAC6沉默的作用。由于 HDAC6 敲低与增强的心肌细胞自噬以及通过与 NLRP3 相互作用抑制 NLRP3 炎性体激活相关，因此它有望成为 DCM 的潜在生物标志物和治疗靶点。

图形概要

1. DCM大鼠中HDAC6表达上调。

2. HDAC6敲低促进心肌细胞自噬，缓解心功能障碍。

3. HDAC6敲低抑制NLRP3炎性体并促进心肌细胞自噬。

4. 沉默HDAC6可促进心肌细胞自噬并抑制细胞凋亡。

5.本研究为DCM提供了新的治疗靶点。