Li Yongming, Meng Xianda, Wang Wenguang, Liu Fu, Hao Zhiru, Yang Yang, Zhao Jinbo, Yin Wensi, Xu Lijuan, Zhao Ruiping, Hu Jiang
Department of Cardiology, Baotou Central HospitalBaotou, China.
Department of Cardiology, Dalian (Municipal) Friendship HospitalDalian, China.
Front Physiol. 2017 Jun 13;8:394. doi: 10.3389/fphys.2017.00394. eCollection 2017.
SIRT6, a member of the NAD (+)-dependent class III deacetylase sirtuin family, plays important roles in the maintenance of cardiovascular homeostasis. Telomere shortening is a risk factor for age-associated diseases, including heart disease. In the present study, we investigated the role of SIRT6 and telomerase in a mouse model of transverse aortic constriction (TAC)-induced heart failure. SIRT6, telomerase reverse transcriptase (TERT), and telomere repeat binding factor (TRF)-1 were significantly downregulated in TAC mice compared with their expression in sham-operated mice. Lentiviral vector-mediated overexpression of SIRT6 upregulated TERT and TRF1 and increased the survival of mice after TAC. Echocardiography and hemodynamic measurements as well as histological analyses indicated that SIRT6 overexpression attenuated TAC-induced heart dysfunction and decreased TAC-induced cardiac inflammatory responses, reducing cardiac fibrosis and decreasing infarct size. Taken together, our findings indicate that SIRT6 protects the myocardium against damage and this effect may be mediated by the modulation of telomeres. Our findings linking SIRT6 and telomere integrity in the heart warrant further investigation into the underlying mechanisms and support SIRT6 as a promising therapeutic target for the treatment of cardiovascular diseases.
SIRT6是烟酰胺腺嘌呤二核苷酸（NAD+）依赖性Ⅲ类脱乙酰酶沉默调节蛋白家族的成员之一，在维持心血管稳态中发挥重要作用。端粒缩短是包括心脏病在内的与年龄相关疾病的一个危险因素。在本研究中，我们在横断主动脉缩窄（TAC）诱导的心力衰竭小鼠模型中研究了SIRT6和端粒酶的作用。与假手术小鼠相比，TAC小鼠中SIRT6、端粒酶逆转录酶（TERT）和端粒重复结合因子（TRF）-1的表达显著下调。慢病毒载体介导的SIRT6过表达上调了TERT和TRF1，并提高了TAC后小鼠的存活率。超声心动图、血流动力学测量以及组织学分析表明，SIRT6过表达减轻了TAC诱导的心脏功能障碍，降低了TAC诱导的心脏炎症反应，减少了心脏纤维化并减小了梗死面积。综上所述，我们的研究结果表明，SIRT6可保护心肌免受损伤，这种作用可能是通过对端粒的调节来介导的。我们关于心脏中SIRT6与端粒完整性之间联系的研究结果值得对潜在机制进行进一步研究，并支持将SIRT6作为治疗心血管疾病的一个有前景的治疗靶点。
