SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis.
SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis.
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DOI：
10.18632/oncotarget.12504
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Varga J
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文献类型：
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作者：
Akamata K;Wei J;Bhattacharyya M;Cheresh P;Bonner MY;Arbiser JL;Raparia K;Gupta MP;Kamp DW;Varga J
组成性成纤维细胞活化是纤维化疾病（包括系统性硬化症（SSc））中器官纤维化的原因，但其潜在机制尚未完全了解，并且缺乏有效的治疗方法。我们研究了线粒体脱乙酰酶sirtuin 3（SIRT 3）的表达及其在纤维化背景下由六氟（一种新型氟化合成honoklavin类似物）的调节。我们发现，通过在正常肺和皮肤成纤维细胞中强制表达或通过六氟处理来增强细胞SIRT 3，阻断了细胞内TGF-β信号传导和纤维化反应，并减轻了SSc成纤维细胞的活化表型。此外，六氟减弱了TGF-β处理的成纤维细胞中的线粒体和细胞溶质活性氧（ROS）积累。值得注意的是，我们发现SIRT 3的表达在SSc皮肤活检和干燥的成纤维细胞中显著降低，并且在正常成纤维细胞中被TGF-β处理抑制。此外，乙酰化MnSOD的组织水平，SIRT 3活性降低的敏感标志物，显着增强病变的皮肤和肺活检SSc患者。用六氟处理的小鼠显示肺和皮肤中博来霉素诱导的纤维化的显著减弱。我们的研究结果揭示了SIRT 3在调节纤维化反应中的细胞自主功能，并证明了一种新型药理学SIRT 3激动剂在体外和体内减轻纤维化的能力。鉴于SSc中与器官纤维化相关的SIRT 3的表达和活性受损，用于增强SIRT 3的药理学方法可能具有治疗潜力。
Constitutive fibroblast activation is responsible for organ fibrosis in fibrotic disorders including systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective therapies are lacking. We investigated the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic honokiol analogue, in the context of fibrosis. We find that augmenting cellular SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts. Moreover, hexafluoro attenuated mitochondrial and cytosolic reactive oxygen species (ROS) accumulation in TGF-β-treated fibroblasts. Remarkably, we found that the expression of SIRT3 was significantly reduced in SSc skin biopsies and explanted fibroblasts, and was suppressed by TGF-β treatment in normal fibroblasts. Moreover, tissue levels of acetylated MnSOD, a sensitive marker of reduced SIRT3 activity, were dramatically enhanced in lesional skin and lung biopsies from SSc patients. Mice treated with hexafluoro showed substantial attenuation of bleomycin-induced fibrosis in the lung and skin. Our findings reveal a cell-autonomous function for SIRT3 in modulating fibrotic responses, and demonstrate the ability of a novel pharmacological SIRT3 agonist to attenuate fibrosis in vitro and in vivo. In light of the impaired expression and activity of SIRT3 associated with organ fibrosis in SSc, pharmacological approaches for augmenting SIRT3 might have therapeutic potential.