SIRT6‑specific inhibitor OSS‑128167 exacerbates diabetic cardiomyopathy by aggravating inflammation and oxidative stress

Huang,Yibo; Zhang,Junkai; Xu,Dongdong; Peng,Yu; Jin,Yuan; Zhang,Lei

doi:10.3892/mmr.2021.12006

SIRT6‑specific inhibitor OSS‑128167 exacerbates diabetic cardiomyopathy by aggravating inflammation and oxidative stress

Authors:
- Yibo Huang
- Junkai Zhang
- Dongdong Xu
- Yu Peng
- Yuan Jin
- Lei Zhang
View Affiliations

Affiliations: 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, Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
Published online on: March 16, 2021 https://doi.org/10.3892/mmr.2021.12006
Article Number: 367
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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.

View Figures

View References

1	Meagher P, Adam M, Civitarese R, Bugyei-Twum A and Connelly KA: Heart failure with preserved ejection fraction in diabetes: Mechanisms and management. Can J Cardiol. 34:632–643. 2018. View Article : Google Scholar : PubMed/NCBI
2	Whiting DR, Guariguata L, Weil C and Shaw J: IDF diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 94:311–321. 2011. View Article : Google Scholar : PubMed/NCBI
3	Al-Quwaidhi AJ, Pearce MS, Sobngwi E, Critchley JA and O'Flaherty M: Comparison of type 2 diabetes prevalence estimates in Saudi Arabia from a validated Markov model against the International Diabetes Federation and other modelling studies. Diabetes Res Clin Pract. 103:496–503. 2014. View Article : Google Scholar : PubMed/NCBI
4	Devereux RB, Roman MJ, Paranicas M, O'Grady MJ, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER and Howard BV: Impact of diabetes on cardiac structure and function: The strong heart study. Circulation. 101:2271–2276. 2000. View Article : Google Scholar : PubMed/NCBI
5	Varma U, Koutsifeli P, Benson VL, Mellor KM and Delbridge LMD: Molecular mechanisms of cardiac pathology in diabetes-Experimental insights. Biochim Biophys Acta Mol Basis Dis. 1864:1949–1959. 2018. View Article : Google Scholar : PubMed/NCBI
6	Dillmann WH: Diabetic cardiomyopathy. Circ Res. 124:1160–1162. 2019. View Article : Google Scholar : PubMed/NCBI
7	Levelt E, Gulsin G, Neubauer S and McCann GP: MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: Pathophysiology and potential metabolic interventions state of the art review. Eur J Endocrinol. 178:R127–R139. 2018. View Article : Google Scholar : PubMed/NCBI
8	Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB and Cai L: Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: Preclinical and clinical evidence. Nat Rev Cardiol. 17:585–607. 2020. View Article : Google Scholar : PubMed/NCBI
9	Jia G, Hill MA and Sowers JR: Diabetic cardiomyopathy: An update of mechanisms contributing to this clinical entity. Circ Res. 122:624–638. 2018. View Article : Google Scholar : PubMed/NCBI
10	Yang F, Qin Y, Wang Y, Li A, Lv J, Sun X, Che H, Han T, Meng S, Bai Y and Wang L: LncRNA KCNQ1OT1 mediates pyroptosis in diabetic cardiomyopathy. Cell Physiol Biochem. 50:1230–1244. 2018. View Article : Google Scholar : PubMed/NCBI
11	Feng W, Lei T, Wang Y, Feng R, Yuan J, Shen X, Wu Y, Gao J, Ding W and Lu Z: GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress. Free Radic Biol Med. 130:128–139. 2019. View Article : Google Scholar : PubMed/NCBI
12	Yu LM, Dong X, Xue XD, Xu S, Zhang X, Xu YL, Wang ZS, Wang Y, Gao H, Liang YX, et al: Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperfusion injury by improving mitochondrial quality control: Role of SIRT6. J Pineal Res. 70:e126982021. View Article : Google Scholar : PubMed/NCBI
13	Jubaidi FF, Zainalabidin S, Mariappan V and Budin SB: Mitochondrial dysfunction in diabetic cardiomyopathy: The possible therapeutic roles of phenolic acids. Int J Mol Sci. 21:60432020. View Article : Google Scholar
14	Finkel T, Deng CX and Mostoslavsky R: Recent progress in the biology and physiology of sirtuins. Nature. 460:587–591. 2009. View Article : Google Scholar : PubMed/NCBI
15	Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC, et al: SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 452:492–496. 2008. View Article : Google Scholar : PubMed/NCBI
16	Yang B, Zwaans BM, Eckersdorff M and Lombard DB: The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability. Cell Cycle. 8:2662–2663. 2009. View Article : Google Scholar : PubMed/NCBI
17	Tennen RI and Chua KF: Chromatin regulation and genome maintenance by mammalian SIRT6. Trends Biochem Sci. 36:39–46. 2011. View Article : Google Scholar : PubMed/NCBI
18	Kugel S and Mostoslavsky R: Chromatin and beyond: The multitasking roles for SIRT6. Trends Biochem Sci. 39:72–81. 2014. View Article : Google Scholar : PubMed/NCBI
19	Khan RI, Nirzhor SSR and Akter R: A review of the recent advances made with SIRT6 and its implications on aging related processes, major human diseases, and possible therapeutic targets. Biomolecules. 8:442018. View Article : Google Scholar
20	Singh CK, Chhabra G, Ndiaye MA, Garcia-Peterson LM, Mack NJ and Ahmad N: The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal. 28:643–661. 2018. View Article : Google Scholar : PubMed/NCBI
21	Arsiwala T, Pahla J, van Tits LJ, Bisceglie L, Gaul DS, Costantino S, Miranda MX, Nussbaum K, Stivala S, Blyszczuk P, et al: Sirt6 deletion in bone marrow-derived cells increases atherosclerosis-Central role of macrophage scavenger receptor 1. J Mol Cell Cardiol. 139:24–32. 2020. View Article : Google Scholar : PubMed/NCBI
22	Jin Z, Xiao Y, Yao F, Wang B, Zheng Z, Gao H, Lv X, Chen L, He Y, Wang W and Lin R: SIRT6 inhibits cholesterol crystal-induced vascular endothelial dysfunction via Nrf2 activation. Exp Cell Res. 387:1117442020. View Article : Google Scholar : PubMed/NCBI
23	Wang L, Han J, Shan P, You S, Chen X, Jin Y, Wang J, Huang W, Wang Y and Liang G: MD2 blockage protects obesity-induced vascular remodeling via activating AMPK/Nrf2. Obesity. 25:1532–1539. 2017. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Fang ZY, Prins JB and Marwick TH: Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications. Endocr Rev. 25:543–567. 2004. View Article : Google Scholar : PubMed/NCBI
26	Lee TW, Kao YH, Chen YJ, Chao TF and Lee TI: Therapeutic potential of vitamin D in AGE/RAGE-related cardiovascular diseases. Cell Mol Life Sci. 76:4103–4115. 2019. View Article : Google Scholar : PubMed/NCBI
27	Kolpakov MA, Sikder K, Sarkar A, Chaki S, Shukla SK, Guo X, Qi Z, Barbery C, Sabri A and Rafiq K: Inflammatory serine proteases play a critical role in the early pathogenesis of diabetic cardiomyopathy. Cell Physiol Biochem. 53:982–998. 2019. View Article : Google Scholar : PubMed/NCBI
28	Zhang X, Zhang Z, Yang Y, Suo Y, Liu R, Qiu J, Zhao Y, Jiang N, Liu C, Tse G, et al: Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits. Cardiovasc Diabetol. 17:1602018. View Article : Google Scholar : PubMed/NCBI
29	Panagopoulou P, Davos CH, Milner DJ, Varela E, Cameron J, Mann DL and Capetanaki Y: Desmin mediates TNF-alpha-induced aggregate formation and intercalated disk reorganization in heart failure. J Cell Biol. 181:761–775. 2008. View Article : Google Scholar : PubMed/NCBI
30	Westermann D, Van Linthout S, Dhayat S, Dhayat N, Schmidt A, Noutsias M, Song XY, Spillmann F, Riad A, Schultheiss HP and Tschöpe C: Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol. 102:500–507. 2007. View Article : Google Scholar : PubMed/NCBI
31	Palomer X, Pizarro-Delgado J and Vazquez-Carrera M: Emerging actors in diabetic cardiomyopathy: Heartbreaker biomarkers or therapeutic targets? Trends Pharmacol Sci. 39:452–467. 2018. View Article : Google Scholar : PubMed/NCBI
32	Sun HJ, Xiong SP, Wu ZY, Cao L, Zhu MY, Moore PK and Bian JS: Induction of caveolin-3/eNOS complex by nitroxyl (HNO) ameliorates diabetic cardiomyopathy. Redox Biol. 32:1014932020. View Article : Google Scholar : PubMed/NCBI
33	Barbeau PA, Holloway TM, Whitfield J, Baechler BL, Quadrilatero J, van Loon LJC, Chabowski A and Holloway GP: α-Linolenic acid and exercise training independently, and additively, decrease blood pressure and prevent diastolic dysfunction in obese Zucker rats. J Physiol. 595:4351–4364. 2017. View Article : Google Scholar : PubMed/NCBI