SIRT6‑specific inhibitor OSS‑128167 exacerbates diabetic cardiomyopathy by aggravating inflammation and oxidative stress.Mol Med Rep. 2021 05; 23(5)MM
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. In vitro, 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) in vitro and in vivo. 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.