Department of Anesthesiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China.
Department of Pain Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China.
Mol Med Rep. 2021 May;23(5). doi: 10.3892/mmr.2021.12006. Epub 2021 Mar 24.
Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, which importantly contributes to the increased mortality of patients with diabetes. The development of DCM is accompanied by numerous pathological mechanisms, including oxidative stress and chronic inflammation. Accordingly, the present study aimed to determine the effects of the sirtuin 6 (SIRT6) inhibitor OSS‑128167 on DCM using a mouse model of streptozotocin (STZ)‑induced diabetes and high glucose (HG)‑treated cardiomyocytes. C57BL/6 mice were intraperitoneally injected with STZ for 5 days to simulate the diabetic cardiomyopathy model. Mice with STZ‑induced diabetes (STZ‑DM1) were orally administered OSS‑128167 (20 or 50 mg/kg) through gavage every other day. The expression of SIRT6 in myocardial tissue was detected using western blotting. Tissue staining (hematoxylin and eosin and Masson's trichrome) was used to characterize myocardial structure, TUNEL fluorescent staining was used to detect myocardial apoptosis, and immunohistochemical staining was used to detect the expression of inflammatory factors in myocardial tissue. Dihydroethidium staining and a malondialdehyde (MDA) detection kit were used to detect the oxidative stress levels in myocardial tissues. , H9c2 cells were pre‑incubated with OSS‑128167 for 1 h and then stimulated with HG (33 mM) for various durations. Expression levels of fibrosis markers, collagen‑1 and transforming growth factor (TGF)‑β, apoptosis‑related proteins, Bax, Bcl‑2 and cleaved‑poly ADP‑ribose polymerase, tumor necrosis factor‑α and the oxidative stress metabolite, 3‑nitrotyrosine were analyzed using western blotting and reverse transcription‑quantitative PCR. Commercially available kits were used to detect the activity of caspase‑3 and the content of MDA in the H9c2 cell line. The corresponding results demonstrated that OSS‑128167 aggravated diabetes‑induced cardiomyocyte apoptosis and fibrosis in mice. Mechanistically, OSS‑128167 was revealed to increase the levels of inflammatory factors and reactive oxygen species (ROS) and . In conclusion, OSS‑128167 facilitated the inflammatory response and promoted the production of ROS while aggravating DCM development. These findings indicated that SIRT6 may target two closely combined and interacting pathological processes, the inflammatory response and oxidative stress, and may serve as a potentially advantageous therapeutic target.
糖尿病心肌病（DCM）是糖尿病的一种严重并发症，可显著增加糖尿病患者的死亡率。DCM 的发展伴随着许多病理机制，包括氧化应激和慢性炎症。因此，本研究旨在使用链脲佐菌素（STZ）诱导的糖尿病小鼠模型和高糖（HG）处理的心肌细胞来确定 SIRT6 抑制剂 OSS-128167 对 DCM 的影响。C57BL/6 小鼠通过腹腔注射 STZ 5 天模拟糖尿病心肌病模型。用 STZ 诱导的糖尿病（STZ-DM1）小鼠通过灌胃隔日给予 OSS-128167（20 或 50mg/kg）。使用 Western blot 检测心肌组织中 SIRT6 的表达。组织染色（苏木精和伊红和 Masson 三色）用于表征心肌结构，TUNEL 荧光染色用于检测心肌细胞凋亡，免疫组织化学染色用于检测心肌组织中炎症因子的表达。二氢乙锭染色和丙二醛（MDA）检测试剂盒用于检测心肌组织中的氧化应激水平。用 OSS-128167 预处理 H9c2 细胞 1 小时，然后用 HG（33mM）刺激不同时间。使用 Western blot 和逆转录定量 PCR 分析纤维化标志物胶原 1 和转化生长因子-β、凋亡相关蛋白 Bax、Bcl-2 和裂解多聚 ADP-核糖聚合酶、肿瘤坏死因子-α和氧化应激代谢物 3-硝基酪氨酸的表达水平。使用商业试剂盒检测 H9c2 细胞系中 caspase-3 的活性和 MDA 的含量。相应的结果表明，OSS-128167 加重了糖尿病诱导的小鼠心肌细胞凋亡和纤维化。从机制上讲，OSS-128167 增加了炎症因子和活性氧（ROS）的水平。综上所述，OSS-128167 促进了炎症反应并促进了 ROS 的产生，同时加重了 DCM 的发展。这些发现表明 SIRT6 可能针对两个紧密结合和相互作用的病理过程，即炎症反应和氧化应激，并可能成为一个有潜在优势的治疗靶点。
