SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation
SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation
复制标题
sirt3通过组蛋白H3去乙酰化介导的FOS抑制可防止心脏纤维化和炎症
DOI：
10.1038/s41392-020-0114-1
复制
发表时间：
2020-02-28
影响因子：
39.3
通讯作者：
Vazquez-Carrera, Manuel
中科院分区：
文献类型：
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作者：
Palomer, Xavier;Silvia Roman-Azcona, M.;Vazquez-Carrera, Manuel
Sirtuin 3（SIRT 3）是一种脱乙酰酶，可调节控制代谢和保护免受氧化应激的蛋白质。SIRT 3活性的调节已被提出作为改善代谢疾病和相关心脏紊乱的有前景的治疗靶点。在这项研究中，我们研究了SIRT 3在心脏炎症和纤维化中的作用，使用了SIRT 3组成性和系统性缺失的雄性小鼠和人心脏AC 16细胞。SIRT 3基因敲除小鼠表现出心脏纤维化和炎症，其特征在于AP-1的转录活性增强。与此一致，SIRT 3在人类和新生大鼠心肌细胞中的过表达部分地阻止了TNF-α诱导的炎症和促纤维化反应。值得注意的是，这些作用与FOS的mRNA和蛋白水平以及AP-1的DNA结合活性的降低有关。最后，我们证明SIRT 3通过其启动子处的特异性组蛋白H3赖氨酸K27去乙酰化来抑制FOS转录。这些发现突出了SIRT 3在通过调节FOS/AP-1通路介导心脏细胞的通常复杂的促纤维化和促炎反应中的重要功能。由于纤维化和炎症在心脏肥大、心力衰竭和糖尿病性心肌病的进展中至关重要，我们的研究结果表明SIRT 3是治疗这些疾病的潜在靶点。
Sirtuin 3 (SIRT3) is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress. Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances. In this study, we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells. SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1. Consistent with this, SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-alpha. Notably, these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1. Finally, we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter. These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway. Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy, heart failure, and diabetic cardiomyopathy, our results point to SIRT3 as a potential target for treating these diseases.