Guo Xiaobin, Yan Fangying, Li Jingyuan, Zhang Chunmei, Bu Peili
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong UniversityJinan, Shandong Province, China.
Am J Transl Res. 2017 Jul 15;9(7):3258-3269. eCollection 2017.
Cardiac fibrosis is a maladaptive response to various stresses, characterized by increased interstitial collagen deposition and progressive cardiac dysfunction. The transdifferentiation of fibroblasts into myofibroblasts is an essential process in the pathogenesis of cardiac fibrosis. SIRT3, as a mitochondrial NAD-dependent histone deacetylase, has been demonstrated beneficial in many cardiovascular diseases. However, the specific mechanism of its protective role in cardiac fibrosis needs to be elucidated further. Here, we determined the role of SIRT3 in cardiac fibrosis by subjecting Sirt3-knockout mice to chronic AngII infusion for four weeks in vivo. In this study, the Sirt3-knockout mice developed more serious cardiac fibrosis compared to wild-type controls. In vitro, primary cardiac fibroblasts from Sirt3-knockout mice transdifferentiated into myofibroblasts spontaneously and this phenotype conversion exaggerated after AngII stimulation. The SIRT3-KO myofibroblasts secret more fibrotic mediators including TGF-β to promote cardiac fibrosis. In addition, the overexpression of SIRT3 by lentivirus transfection attenuated myofibroblasts transdifferentiation. We further demonstrated that SIRT3 directly binds to and deacetylates STAT3 to inhibit its activity. Sequentially the downstream factor, known as NFATc2, showed a reduced expression. Taken together, these results revealed that SIRT3 can protect against cardiac fibrosis by inhibiting myofibroblasts transdifferentiation via the STAT3-NFATc2 signaling pathway.
心脏纤维化是对各种应激的一种适应性不良反应，其特征是间质胶原沉积增加和进行性心脏功能障碍。成纤维细胞向肌成纤维细胞的转分化是心脏纤维化发病机制中的一个重要过程。SIRT3作为一种线粒体NAD依赖性组蛋白脱乙酰酶，已被证明在许多心血管疾病中具有有益作用。然而，其在心脏纤维化中保护作用的具体机制仍需进一步阐明。在此，我们通过对Sirt3基因敲除小鼠进行四周的慢性血管紧张素II体内输注，确定了SIRT3在心脏纤维化中的作用。在本研究中，与野生型对照相比，Sirt3基因敲除小鼠发生了更严重的心脏纤维化。在体外，Sirt3基因敲除小鼠的原代心脏成纤维细胞自发转分化为肌成纤维细胞，且这种表型转化在血管紧张素II刺激后加剧。SIRT3基因敲除的肌成纤维细胞分泌更多包括转化生长因子-β在内的纤维化介质，以促进心脏纤维化。此外，通过慢病毒转染过表达SIRT3可减弱肌成纤维细胞的转分化。我们进一步证明，SIRT3直接结合并使信号转导和转录激活因子3（STAT3）去乙酰化以抑制其活性。随后，下游因子活化T细胞核因子2（NFATc2）的表达降低。综上所述，这些结果表明，SIRT3可通过STAT3-NFATc2信号通路抑制肌成纤维细胞转分化，从而预防心脏纤维化。
