Inhibition of Sestrin2 overexpression in diabetic cardiomyopathy ameliorates cardiac injury via restoration of mitochondrial function

Zhang,Xiaodan; Deng,Xiaoyi; Ye,Huiyu; Chen,Zhishan; Li,Wangen

doi:10.3892/etm.2022.11191

Inhibition of Sestrin2 overexpression in diabetic cardiomyopathy ameliorates cardiac injury via restoration of mitochondrial function

Authors:
- Xiaodan Zhang
- Xiaoyi Deng
- Huiyu Ye
- Zhishan Chen
- Wangen Li
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Affiliations: Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
Published online on: February 4, 2022 https://doi.org/10.3892/etm.2022.11191
Article Number: 265
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mitochondrial dysfunction‑induced apoptosis plays a crucial role in the progression of diabetic cardiomyopathy (DCM). Sestrin2 is an important oxidative stress response protein and is involved in the maintenance of mitochondrial function, especially under stress. The aim of the present study was to investigate the role of Sestrin2 in DCM and to explore the underlying mechanisms. H9c2 cardiomyocytes were induced with high glucose (HG) medium (33 mmol/l glucose) for an in vitro DCM model. C57BL/6 mice were induced for the in vivo DCM model by intraperitoneal streptozotocin injection. H9c2 cardiomyocytes were exposed to HG and infected with lentiviruses to express Sestrin2 short hairpin RNA (shRNA). The study found that cell viability and mitochondrial function were impaired while cell apoptosis and oxidative stress were increased in DCM. Sestrin2 was significantly upregulated in myocardial tissues of DCM mice and H9c2 cardiomyocytes in HG conditions. Downregulation of Sestrin2 increased cell viability, decreased cell apoptosis, and attenuated oxidative stress in H9c2 cells exposed to HG. Moreover, HG‑induced mitochondrial injury was alleviated by Sestrin2 silencing. In conclusion, our finding indicated that the inhibition of enhanced Sestrin2 expression ameliorates cardiac injury in DCM, which might be largely attributed to the restoration of mitochondrial function.

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1	Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, et al: 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 41:255–323. 2020.PubMed/NCBI View Article : Google Scholar
2	Jia G, Whaley-Connell A and Sowers JR: Diabetic cardiomyopathy: A hyperglycaemia and insulin resistance-induced heart disease. Diabetologia. 61:21–28. 2018.PubMed/NCBI View Article : Google Scholar
3	Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, Ocorr K, Rllisman MH, Bodmer R, Bier E and Karin M: Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science. 327:1223–1228. 2010.PubMed/NCBI View Article : Google Scholar
4	Gao A, Li F, Zhou Q and Chen L: Sestrin2 as a potential therapeutic target for cardiovascular diseases. Pharmacol Res. 159(104990)2020.PubMed/NCBI View Article : Google Scholar
5	Ding B, Parmigiani A, Divakaruni AS, Archer K, Murphy AN and Budanov AV: Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death. Sci Rep. 6(2253)2016.PubMed/NCBI View Article : Google Scholar
6	Livak KJ and Schmittgen TD: Analysis of reactive gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
7	Zhang X, Zhong Z and Li W: Downregulation of TRAP1 aggravates injury of H9c2 cardiomyocytes in a hyperglycemic state. Exp Ther Med. 18:2681–2686. 2019.PubMed/NCBI View Article : Google Scholar
8	Federico M, Fuente S, Palomeque J and Sheu S: The role of mitochondria in metabolic disease: A special emphasis on heart dysfunction. J Physiol. 599:3477–3493. 2021.PubMed/NCBI View Article : Google Scholar
9	Kubli D and Gustafsson Å: Unbreak my heart: Targeting mitochondrial autophagy in diabetic cardiomyopathy. Antioxid Redox Signal. 22:1527–1544. 2015.PubMed/NCBI View Article : Google Scholar
10	Budanov AV, Lee JH and Karin M: Stressin Sestrins take an aging fight. EMBO Mol Med. 2:388–400. 2010.PubMed/NCBI View Article : Google Scholar
11	Sun W, Wang Y, Zheng Y and Quan N: The emerging role of Sestrin2 in cell metabolism, and cardiovascular and age-related diseases. Aging Dis. 11:154–163. 2020.PubMed/NCBI View Article : Google Scholar
12	Quan N, Li X, Zhang J, Han Y, Sun W, Ren D, Tong Q and Li J: Substrate metabolism regulated by Sestrin2-mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart. Redox Biol. 36(101637)2020.PubMed/NCBI View Article : Google Scholar
13	Lee JH, Budanov AV, Talukdar S, Park EJ, Park HL, Park HW, Bandyopadhyay G, Li N, Aghajan M, Jang I, et al: Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. Cell Metab. 16:311–321. 2012.PubMed/NCBI View Article : Google Scholar
14	Lin Q, Ma Y, Chen Z, Hu J, Chen C, Fan Y, Liang W and Ding G: Sestrin-2 regulates podocyte mitochondrial dysfunction and apoptosis under high-glucose conditions via AMPK. Int J Mol Med. 45:1361–1372. 2020.PubMed/NCBI View Article : Google Scholar
15	Sundararajan S, Jayachandran I, Balasubramanyam M, Mohan V, Venkatesan B and Manickam N: Sestrin2 regulates monocyte activation through AMPK-mTOR nexus under high-glucose and dyslipidemic conditions. J Cell Biochem: Nov 18, 2018 (Epub ahead of print). doi: 10.1002/jcb.28102.
16	Hwang H, Kim JW, Chung HS, Seo JA, Kim SG, Kim NH, Choi KM, Baik SH and Yoo HJ: Knockdown of Sestrin2 increases lipopolysaccharide-induced oxidative stress, apoptosis, and fibrotic reactions in H9c2 cells and heart tissues of mice via an AMPK-dependent mechanism. Mediators Inflamm. 2018(6209140)2018.PubMed/NCBI View Article : Google Scholar
17	Dong B, Xue R, Sun Y, Dong Y and Liu C: Sestrin 2 attenuates neonatal rat cardiomyocyte hypertrophy induced by phenylephrine via inhibiting ERK1/2. Mol Cell Biochem. 433:113–123. 2017.PubMed/NCBI View Article : Google Scholar
18	Budanov AV, Shoshani T, Faerman A, Zelin E, Kamer I, Kalinski H, Gorodin S, Fishman A, Chajut A, Einat P, et al: Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene. 21:6017–6031. 2002.PubMed/NCBI View Article : Google Scholar
19	Wang H, Li N, Shao X, Li J, Guo L, Yu X, Sun Y, Hao J, Xiang J, Li X and Han X: Increased plasma sestrin2 concentrations in patients with chronic heart failure and predicted the occurrence of major adverse cardiac events: A 36-month follow-up cohort study. Clin Chim Acta. 495:338–344. 2019.PubMed/NCBI View Article : Google Scholar
20	Kishimoto Y, Aoyama M, Saita E, Ikegami Y, Ohmori R, Kondo K and Momiyama Y: Association between plasma Sestrin2 Levels and the presence and severity of coronary artery disease. Dis Markers. 2020(7439574)2020.PubMed/NCBI View Article : Google Scholar
21	Kishimoto Y, Saita E, Ohmori R, Kondo K and Momiyama Y: Plasma sestrin2 concentrations and carotid atherosclerosis. Clin Chim Acta. 504:56–59. 2020.PubMed/NCBI View Article : Google Scholar
22	Chung HS, Hwang H, Hwang SY, Kim NH, Seo JA, Kim SG, Kim NH, Sei Baik H, Choi KM and Yoo HJ: Association of serum Sestrin2 level with metabolic risk factors in newly diagnosed drug-naïve type 2 diabetes. Diabetes Res Clin Pract. 144:34–41. 2018.PubMed/NCBI View Article : Google Scholar
23	Sundararajan S, Jayachandran I, Subramanian SC, Anjana RM, Balasubramanyam M, Mohan V, Venkatesan B and Manickam N: Decreased Sestrin levels in patients with type 2 diabetes and dyslipidemia and their association with the severity of atherogenic index. J Endocrinol Invest. 44:1395–1405. 2021.PubMed/NCBI View Article : Google Scholar
24	Mohany KM and Rugaie OA: Association of serum sestrin 2 and betatrophin with serum neutrophil gelatinase associated lipocalin levels in type 2 diabetic patients with diabetic nephropathy. J Diabetes Metab Disord. 19:249–256. 2020.PubMed/NCBI View Article : Google Scholar