Zhang Yuan, Zhang Yi
Department of Cardiology, Huaihe Hospital, Henan University, 8 Baobei Rd., Kaifeng, 475000, China.
Department of Cardiology, The Fifth People's Hospital of Shenzhen City, 47 Youyi Rd., Shenzhen, 518001, China.
Biochem Biophys Res Commun. 2016 Apr 29;473(2):388-95. doi: 10.1016/j.bbrc.2016.02.111. Epub 2016 Mar 3.
Diabetic cardiomyopathy is an essential complication of diabetes and characterized by persistent diastolic dysfunction, leading to myocardial fibrosis. Oxidative stress and inflammation lead to cell damage and are implicated in many disease states. In our study, we evaluated the effects of toll-like receptor 6 (TLR6) in cardiac remodeling. We established a mouse model of myocardial fibrosis with diabetes using 30% fructose. In comparison to HF-feeding control mice, TLR6 deficient mice developed less myocardial fibrosis with lower myocardial injury marker enzymes and AngII and aldosterone (ALD). In addition, Collagen type I/III, alpha smooth muscle-actin (α-SMA) and FSP-1, as typical markers of myocardial fibrosis formation, were found to be reduced due to TLR6 knockout in HF-induced mice. HF-feeding mice developed myocardial fibrosis with lower SOD activity, high level of MDA, O2(-) and H2O2 and increased serum pro-inflammatory cytokines, whereas TLR6 deficient mice after HF-administration were protected from myocardial fibrosis progression significantly. HF-feeding mice also displayed lower Nrf2 and higher XO levels, which was not observed in TLR6 deficient mice after HF-feeding. Furthermore, NF-κB pathway was inactivated for TLR6 knockout compared with HF-feeding mice. In vitro, fructose directly up-regulated α-SMA, TGF-β1, Collagen type I/III and FSP-1 via ROS production and NF-κB phosphorylation as well as pro-inflammatory cytokines releasing, which were inhibited for TLR6 deficiency. Taken together, TLR6 contributed to myocardial fibrosis progression, at least partly, through oxidative stress and inflammatory response, providing a potential therapeutic strategy for myocardial fibrosis treatment.
糖尿病性心肌病是糖尿病的一种重要并发症，其特征为持续性舒张功能障碍，进而导致心肌纤维化。氧化应激和炎症会导致细胞损伤，并与多种疾病状态有关。在我们的研究中，我们评估了Toll样受体6（TLR6）在心脏重塑中的作用。我们使用30%的果糖建立了糖尿病心肌纤维化小鼠模型。与高脂饲料喂养的对照小鼠相比，TLR6缺陷小鼠心肌纤维化程度较轻，心肌损伤标志物酶、血管紧张素II和醛固酮（ALD）水平较低。此外，作为心肌纤维化形成的典型标志物，I/III型胶原蛋白、α平滑肌肌动蛋白（α-SMA）和FSP-1在高脂诱导的小鼠中因TLR6基因敲除而减少。高脂饲料喂养的小鼠出现心肌纤维化，超氧化物歧化酶（SOD）活性降低，丙二醛（MDA）、超氧阴离子（O2-）和过氧化氢（H2O2）水平升高，血清促炎细胞因子增加，而高脂饲料喂养后给予TLR6缺陷小鼠可显著防止心肌纤维化进展。高脂饲料喂养的小鼠还表现出较低的核因子E2相关因子2（Nrf2）水平和较高的黄嘌呤氧化酶（XO）水平，而高脂饲料喂养后TLR6缺陷小鼠未观察到这种情况。此外，与高脂饲料喂养的小鼠相比，TLR6基因敲除使核因子κB（NF-κB）通路失活。在体外，果糖通过活性氧生成、NF-κB磷酸化以及促炎细胞因子释放直接上调α-SMA、转化生长因子-β1（TGF-β1）、I/III型胶原蛋白和FSP-1，而TLR6缺陷可抑制这些作用。综上所述，TLR6至少部分通过氧化应激和炎症反应促进心肌纤维化进展，为心肌纤维化治疗提供了一种潜在的治疗策略。
