Wei Huili, Qu Hua, Wang Hang, Ji Baolan, Ding Yao, Liu Dan, Duan Yang, Liang Huimin, Peng Chuan, Xiao Xiaoqiu, Deng Huacong
Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing 400016, China.
Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing 400016, China.
J Steroid Biochem Mol Biol. 2017 Apr;168:71-90. doi: 10.1016/j.jsbmb.2017.02.007. Epub 2017 Feb 17.
Diabetic cardiomyopathy (DCM) can increase the risk of heart failure and death in diabetic patients. However, no effective approaches are available to prevent its progression and development. Studies have shown that vitamin D is greatly implicated in cardiac hypertrophy and fibrosis, and there is a high prevalence of vitamin D deficiency in diabetic patients. In this study, we investigated whether 1,25-Dihydroxyvitamin-D3 (1,25D3) can improve DCM through a vitamin D receptor (VDR)-dependent mechanism associated with autophagy and the β-catenin/T-cell factor/lymphoid enhancer factor (TCF4)/glycogen synthase kinase-3β (GSK-3β)/mammalian target of rapamycin (mTOR) pathway. In this study, streptozotocin (STZ)-induced type 1 diabetic rats were established and were treated with 1,25D3 and/or chloroquine and/or VDR gene silencing for 8 weeks before being sacrificed. Compared with untreated diabetic rats, 1,25D3 partly attenuated the myocardial hypertrophy and interstitial fibrosis, improved cardiac function and restored the impaired cardiac autophagy in diabetic rats, all of which were reversed by silencing the VDR gene in diabetic rats. In high-glucose cultured H9C2 cells, 1,25D3 increased autophagy in a dose-dependent manner. Besides, the β-catenin/TCF4/GSK-3β and mTOR signaling were activated both in diabetic rats and in high-glucose cultured H9C2 cells. Treatment with 1,25D3 inhibited the β-catenin/TCF4/GSK-3β and mTOR signaling in H9C2 cells, whereas co-treatment with lithium chloride (LiCl) reversed this situation and abolished the beneficial effect of 1,25D3 on autophagy. These data suggest that 1,25D3 may improve DCM in type 1 diabetic rats by modulating autophagy through the β-catenin/TCF4/GSK-3β and mTOR pathway. Vitamin D may exist as a new therapeutic target for the treatment of DCM.
糖尿病心肌病（DCM）会增加糖尿病患者发生心力衰竭和死亡的风险。然而，目前尚无有效的方法来预防其进展和发展。研究表明，维生素D与心肌肥大和纤维化密切相关，且糖尿病患者中维生素D缺乏的发生率很高。在本研究中，我们探究了1,25-二羟基维生素D3（1,25D3）是否能通过与自噬以及β-连环蛋白/T细胞因子/淋巴样增强因子（TCF4）/糖原合酶激酶-3β（GSK-3β）/雷帕霉素哺乳动物靶蛋白（mTOR）通路相关的维生素D受体（VDR）依赖性机制来改善DCM。在本研究中，构建了链脲佐菌素（STZ）诱导的1型糖尿病大鼠模型，并在处死前用1,25D3和/或氯喹和/或VDR基因沉默处理8周。与未治疗的糖尿病大鼠相比，1,25D3部分减轻了糖尿病大鼠的心肌肥大和间质纤维化，改善了心脏功能并恢复了受损的心脏自噬，而在糖尿病大鼠中沉默VDR基因可逆转所有这些作用。在高糖培养的H9C2细胞中，1,25D3以剂量依赖性方式增加自噬。此外，β-连环蛋白/TCF4/GSK-3β和mTOR信号通路在糖尿病大鼠和高糖培养的H9C2细胞中均被激活。用1,25D3处理可抑制H9C2细胞中的β-连环蛋白/TCF4/GSK-3β和mTOR信号通路，而与氯化锂（LiCl）联合处理可逆转这种情况并消除1,25D3对自噬的有益作用。这些数据表明，1,25D3可能通过β-连环蛋白/TCF4/GSK-3β和mTOR通路调节自噬来改善1型糖尿病大鼠的DCM。维生素D可能作为治疗DCM的新治疗靶点。
