miR‑155 modulates high glucose‑induced cardiac fibrosis via the Nrf2/HO‑1 signaling pathway

Li,Yu; Duan,Jing‑Zhu; He,Qian; Wang,Chong‑Quan

doi:10.3892/mmr.2020.11495

miR‑155 modulates high glucose‑induced cardiac fibrosis via the Nrf2/HO‑1 signaling pathway

Authors:
- Yu Li
- Jing‑Zhu Duan
- Qian He
- Chong‑Quan Wang
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Affiliations: Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Department of Respiratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
Published online on: September 7, 2020 https://doi.org/10.3892/mmr.2020.11495
Pages: 4003-4016

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Abstract

Cardiac fibrosis is a major pathological manifestation of diabetic cardiomyopathy, which is a leading cause of mortality in patients with diabetes. MicroRNA (miR)‑155 is upregulated in cardiomyocytes in cardiac fibrosis, and the aim of the present study was to investigate if the inhibition of miR‑155 was able to ameliorate cardiac fibrosis by targeting the nuclear factor erythroid‑2‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1) signaling pathway. H9C2 rat cardiomyocytes were cultured with high glucose (HG; 30 mM) to establish an in vitro cardiac fibrosis model that mimicked diabetic conditions; a miR‑155 inhibitor and a miR‑155 mimic were transfected into H9C2 cells. Following HG treatment, H9C2 cells exhibited increased expression levels of miR‑155 and the fibrosis markers collagen I and α‑smooth muscle actin (α‑SMA). In addition, the expression levels of endonuclear Nrf2 and HO‑1 were decreased, but the expression level of cytoplasmic Nrf2 was increased. Moreover, oxidative stress, mitochondrial damage and cell apoptosis were significantly increased, as indicated by elevated reactive oxygen species, malonaldehyde and monomeric JC‑1 expression levels. In addition, superoxide dismutase expression was attenuated and there was an increased expression level of released cytochrome‑c following HG treatment. Furthermore, it was demonstrated that expression levels of Bcl‑2 and uncleaved Poly (ADP‑ribose) polymerase were downregulated, whereas Bax, cleaved caspase‑3 and caspase‑9 were upregulated after HG treatment. However, the miR‑155 inhibitor significantly restored Nrf2 and HO‑1 expression levels, and reduced oxidative stress levels, the extent of mitochondrial damage and the number of cells undergoing apoptosis. Additionally, the miR‑155 inhibitor significantly reversed the expression levels of collagen I and α‑SMA, thus ameliorating fibrosis. Furthermore, the knockdown of Nrf2 reversed the above effects induced by the miR‑155 inhibitor. In conclusion, the miR‑155 inhibitor may ameliorate diabetic cardiac fibrosis by reducing the accumulation of oxidative stress‑related molecules, and preventing mitochondrial damage and cardiomyocyte apoptosis by enhancing the Nrf2/HO‑1 signaling pathway. This mechanism may facilitate the development of novel targets to prevent cardiac fibrosis in patients with diabetes.

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1	Worke LJ, Barthold JE, Seelbinder B, Novak T, Main RP, Harbin SL and Neu CP: Densification of type I collagen matrices as a model for cardiac fibrosis. Adv Healthc Mater. 6:17001142017. View Article : Google Scholar
2	Murtha LA, Schuliga MJ, Mabotuwana NS, Hardy SA, Waters DW, Burgess JK, Knight DA and Boyle AJ: The processes and mechanisms of cardiac and pulmonary fibrosis. Front Physiol. 8:7772017. View Article : Google Scholar : PubMed/NCBI
3	Louridas GE and Lourida KG: Systems biology and biomechanical model of heart failure. Curr Cardiol Rev. 8:220–230. 2012. View Article : Google Scholar : PubMed/NCBI
4	Zhang WW, Bai F, Wang J, Zheng RH, Yang LW, James EA and Zhao ZQ: Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor. Drug Des Devel Ther. 11:3019–3033. 2017. View Article : Google Scholar : PubMed/NCBI
5	Michael LH, Taffet GE, Entman ML, Reddy AK, Hartley CJ and Frangogiannis NG: Chapter 2.6-The Cardiovascular System. The Laboratory Mouse. Second Edition. Hedrich HJ: Academic Press; Boston: pp. 241–270. 2012, View Article : Google Scholar
6	Asbun J and Villarreal FJ: The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol. 47:693–700. 2006. View Article : Google Scholar : PubMed/NCBI
7	Bharati S and Lev M: Cardiac conduction system involvement in sudden death of obese young people. Am Heart J. 129:273–281. 1995. View Article : Google Scholar : PubMed/NCBI
8	Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, Tschoepe D, Doehner W, Greene SJ, Senni M, et al: Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail. 3:136–145. 2015. View Article : Google Scholar : PubMed/NCBI
9	Wei Y, Yan X, Yan L, Hu F, Ma W, Wang Y, Lu S, Zeng Q and Wang Z: Inhibition of microRNA-155 ameliorates cardiac fibrosis in the process of angiotensin II-induced cardiac remodeling. Mol Med Rep. 16:7287–7296. 2017. View Article : Google Scholar : PubMed/NCBI
10	Quiat D and Olson EN: MicroRNAs in cardiovascular disease: From pathogenesis to prevention and treatment. J Clin Invest. 123:11–18. 2013. View Article : Google Scholar : PubMed/NCBI
11	Zhang D, Cui Y, Li B, Luo X, Li B and Tang Y: miR-155 regulates high glucose-induced cardiac fibrosis via the TGF-β signaling pathway. Mol Biosyst. 13:215–224. 2016. View Article : Google Scholar : PubMed/NCBI
12	Seok HY, Chen J, Kataoka M, Huang ZP, Ding J, Yan J, Hu X and Wang DZ: Loss of MicroRNA-155 protects the heart from pathological cardiac hypertrophy. Circ Res. 114:1585–1595. 2014. View Article : Google Scholar : PubMed/NCBI
13	Tran PL, Tran PT, Tran HNK, Lee S, Kim O, Min BS and Lee JH: A prenylated flavonoid, 10-oxomornigrol F, exhibits anti-inflammatory effects by activating the Nrf2/heme oxygenase-1 pathway in macrophage cells. Int Immunopharmacol. 55:165–173. 2018. View Article : Google Scholar : PubMed/NCBI
14	Chen RR, Fan XH, Chen G, Zeng GW, Xue YG, Liu XT and Wang C: Irisin attenuates angiotensin II-induced cardiac fibrosis via Nrf2 mediated inhibition of ROS/ TGFβ1/Smad2/3 signaling axis. Chem Biol Interact. 302:11–21. 2019. View Article : Google Scholar : PubMed/NCBI
15	Meng Z, Li HY, Si CY, Liu YZ and Teng S: Asiatic acid inhibits cardiac fibrosis throughNrf2/HO-1 and TGF-β1/Smads signaling pathways in spontaneous hypertension rats. Int Immunopharmacol. 74:1057122019. View Article : Google Scholar : PubMed/NCBI
16	Jeong JY, Cha HJ, Choi EO, Kim CH, Kim GY, Yoo YH, Hwang HJ, Park HT, Yoon HM and Choi YH: Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of baicalein against oxidative stress-induced DNA damage and apoptosis in HEI193 Schwann cells. Int J Med Sci. 16:145–155. 2019. View Article : Google Scholar : PubMed/NCBI
17	Abraham NG and Kappas A: Heme oxygenase and the cardiovascular-renal system. Free Radic Biol Med. 39:1–25. 2005. View Article : Google Scholar : PubMed/NCBI
18	Chen M, Samuel VP, Wu Y, Dang M, Lin Y, Sriramaneni R, Sah SK, Chinnaboina GK and Zhang G: Nrf2/HO-1 mediated protective activity of genistein against doxorubicin-induced cardiac toxicity. J Environ Pathol Toxicol Oncol. 38:143–152. 2019. View Article : Google Scholar : PubMed/NCBI
19	Chen C, Jiang X, Gu S and Zhang Z: MicroRNA-155 regulates arsenite-induced malignant transformation by targeting Nrf2-mediated oxidative damage in human bronchial epithelial cells. Toxicol Lett. 278:38–47. 2017. View Article : Google Scholar : PubMed/NCBI
20	Wan C, Han R, Liu L, Zhang F, Li F, Xiang M and Ding W: Role of miR-155 in fluorooctane sulfonate-induced oxidative hepatic damage via the Nrf2-dependent pathway. Toxicol Appl Pharmacol. 295:85–93. 2016. View Article : Google Scholar : PubMed/NCBI
21	Gu S, Lai Y, Chen H, Liu Y and Zhang Z: miR-155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. Sci Rep. 7:121552017. View Article : Google Scholar : PubMed/NCBI
22	Hu M, Ye P, Liao H, Chen M and Yang F: Metformin protects H9C2 cardiomyocytes from high-glucose and hypoxia/reoxygenation injury via inhibition of reactive oxygen species generation and inflammatory responses: Role of AMPK and JNK. J Diabetes Res. 2016:29619542016. View Article : Google Scholar : PubMed/NCBI
23	Bugyei-Twum A, Advani A, Advani SL, Zhang Y, Thai K, Kelly DJ and Connelly KA: High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy. Cardiovasc Diabetol. 13:892014. 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	Ahmad A and Abdel Moneim AE: Indigofera oblongifolia prevents lead acetate-induced hepatotoxicity, oxidative stress, fibrosis and apoptosis in rats. PLoS One. 11:e01589652016. View Article : Google Scholar : PubMed/NCBI
26	Hüttemann M, Pecina P, Rainbolt M, Sanderson TH, Kagan VE, Samavati L, Doan JW and Lee I: The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell: From respiration to apoptosis. Mitochondrion. 11:369–381. 2011. View Article : Google Scholar : PubMed/NCBI
27	Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C and Kroemer G: Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 13:1423–1433. 2006. View Article : Google Scholar : PubMed/NCBI
28	Tsutsui H, Kinugawa S and Matsushima S: Mitochondrial oxidative stress and dysfunction in myocardial remodelling. Cardiovasc Res. 81:449–456. 2008. View Article : Google Scholar : PubMed/NCBI
29	Opferman JT and Kothari A: Anti-apoptotic BCL-2 family members in development. Cell Death Differ. 25:37–45. 2018. View Article : Google Scholar : PubMed/NCBI
30	Czabotar PE, Lessene G, Strasser A and Adams JM: Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat Rev Mol Cell Biol. 15:49–63. 2014. View Article : Google Scholar : PubMed/NCBI
31	Ma ZG, Yuan YP, Wu HM, Zhang X and Tang QZ: Cardiac fibrosis: New insights into the pathogenesis. Int J Biol Sci. 14:1645–1657. 2018. View Article : Google Scholar : PubMed/NCBI
32	Fang L, Murphy AJ and Dart AM: A Clinical perspective of anti-fibrotic therapies for cardiovascular disease. Front Pharmacol. 8:186. 2017. View Article : Google Scholar : PubMed/NCBI
33	Brahma MK, Pepin ME and Wende AR: My sweetheart is broken: Role of glucose in diabetic cardiomyopathy. Diabetes Metab J. 41:1–9. 2017. View Article : Google Scholar : PubMed/NCBI
34	Costantino S, Paneni F, Lüscher TF and Cosentino F: MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart. Eur Heart J. 37:572–576. 2016. View Article : Google Scholar : PubMed/NCBI
35	Huang Y, Liu Y, Li L, Su B, Yang L, Fan W, Yin Q, Chen L, Cui T, Zhang J, et al: Involvement of inflammation-related miR-155 and miR-146a in diabetic nephropathy: implications for glomerular endothelial injury. BMC Nephrol. 15:1422014. View Article : Google Scholar : PubMed/NCBI
36	Gao J, Zhao G, Li W, Zhang J, Che Y, Song M, Gao S, Zeng B and Wang Y: miR-155 targets PTCH1 to mediate endothelial progenitor cell dysfunction caused by high glucose. Exp Cell Res. 366:55–62. 2018. View Article : Google Scholar : PubMed/NCBI
37	Palma CA, Al Sheikha D, Lim TK, Bryant A, Vu TT, Jayaswal V and Ma DD: MicroRNA-155 as an inducer of apoptosis and cell differentiation in Acute Myeloid Leukaemia. Mol Cancer. 13:792014. View Article : Google Scholar : PubMed/NCBI
38	Song Y, Wen L, Sun J, Bai W, Jiao R, Hu Y, Peng X, He Y and Ou S: Cytoprotective mechanism of ferulic acid against high glucose-induced oxidative stress in cardiomyocytes and hepatocytes. Food Nutr Res. 60:303232016. View Article : Google Scholar : PubMed/NCBI
39	You S, Qian J, Sun C, Zhang H, Ye S, Chen T, Xu Z, Wang J, Huang W and Liang G: An Aza resveratrol-chalcone derivative 6b protects mice against diabetic cardiomyopathy by alleviating inflammation and oxidative stress. J Cell Mol Med. 22:1931–1943. 2018. View Article : Google Scholar : PubMed/NCBI
40	Ying Y, Jin J, Ye L, Sun P, Wang H and Wang X: Phloretin prevents diabetic cardiomyopathy by dissociating Keap1/Nrf2 complex and inhibiting oxidative stress. Front Endocrinol (Lausanne). 9:7742018. View Article : Google Scholar : PubMed/NCBI
41	Li L, Luo W, Qian Y, Zhu W, Qian J, Li J, Jin Y, Xu X and Liang G: Luteolin protects against diabetic cardiomyopathy by inhibiting NF-κB-mediated inflammation and activating the Nrf2-mediated antioxidant responses. Phytomedicine. 59:1527742019. View Article : Google Scholar : PubMed/NCBI
42	Tsai CY, Wen SY, Cheng SY, Wang CH, Yang YC, Viswanadha VP, Huang CY and Kuo WW: Nrf2 activation as a protective feedback to limit cell death in high glucose-exposed cardiomyocytes. J Cell Biochem. 118:1659–1669. 2017. View Article : Google Scholar : PubMed/NCBI
43	Zhou L, Xu DY, Sha WG, Shen L, Lu GY, Yin X and Wang MJ: High glucose induces renal tubular epithelial injury via Sirt1/NF-kappaB/microR-29/Keap1 signal pathway. J Transl Med. 13:3522015. View Article : Google Scholar : PubMed/NCBI
44	Yang ZB, Chen WW, Chen HP, Cai SX, Lin JD and Qiu LZ: MiR-155 aggravated septic liver injury by oxidative stress-mediated ER stress and mitochondrial dysfunction via targeting Nrf-2. Exp Mol Pathol. 105:387–394. 2018. View Article : Google Scholar : PubMed/NCBI
45	Chen J, Li C, Liu W, Yan B, Hu X and Yang F: miRNA-155 silencing reduces sciatic nerve injury in diabetic peripheral neuropathy. J Mol Endocrinol. 63:227–238. 2019. View Article : Google Scholar : PubMed/NCBI
46	Kosuru R, Kandula V, Rai U, Prakash S, Xia Z and Singh S: Pterostilbene decreases cardiac oxidative stress and inflammation via activation of AMPK/Nrf2/HO-1 pathway in fructose-fed diabetic rats. Cardiovasc Drugs Ther. 32:147–163. 2018. View Article : Google Scholar : PubMed/NCBI
47	Holmström KM, Kostov RV and Dinkova-Kostova AT: The multifaceted role of Nrf2 in mitochondrial function. Curr Opin Toxicol. 1:80–91. 2016. View Article : Google Scholar : PubMed/NCBI
48	Liang J, Li L, Sun Y, He W, Wang X and Su Q: The protective effect of activating Nrf2/HO-1 signaling pathway on cardiomyocyte apoptosis after coronary microembolization in rats. BMC Cardiovasc Disord. 17:2722017. View Article : Google Scholar : PubMed/NCBI
49	Zhang YF, Meng NN, Li HZ, Wen YJ, Liu JT, Zhang CL, Yuan XH and Jin XD: Effect of naringin on oxidative stress and endoplasmic reticulum stress in diabetic cardiomyopathy. Zhongguo Zhong Yao Za Zhi. 43:596–602. 2018.(In Chinese). PubMed/NCBI
50	Peng C, Ma J, Gao X, Tian P, Li W and Zhang L: High glucose induced oxidative stress and apoptosis in cardiac microvascular endothelial cells are regulated by FoxO3a. PLoS One. 8:e797392013. View Article : Google Scholar : PubMed/NCBI
51	Wang R, Lu L, Guo Y, Lin F, Chen H, Chen W and Chen M: Effect of glucagon-like peptide-1 on high-glucose-induced oxidative stress and cell apoptosis in human endothelial cells and its underlying mechanism. J Cardiovasc Pharmacol. 66:135–140. 2015. View Article : Google Scholar : PubMed/NCBI
52	Zhang M, Niu X, Hu J, Yuan Y, Sun S, Wang J, Yu W, Wang C, Sun D and Wang H: Lin28a Protects against hypoxia/reoxygenation induced cardiomyocytes apoptosis by alleviating mitochondrial dysfunction under high glucose/high fat conditions. PLoS One. 9:e1105802014. View Article : Google Scholar : PubMed/NCBI
53	Gao CL, Zhu C, Zhao YP, Chen XH, Ji CB, Zhang CM, Zhu JG, Xia ZK, Tong ML and Guo XR: Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes. Mol Cell Endocrinol. 320:25–33. 2010. View Article : Google Scholar : PubMed/NCBI
54	Hung KY, Liu SY, Yang TC, Liao TL and Kao SH: High-dialysate-glucose-induced oxidative stress and mitochondrial-mediated apoptosis in human peritoneal mesothelial cells. Oxid Med Cell Longev. 2014:642793. 2014. View Article : Google Scholar : PubMed/NCBI
55	Ho FM, Liu SH, Liau CS, Huang PJ and Lin-Shiau SY: High glucose-induced apoptosis in human endothelial cells is mediated by sequential activations of c-Jun NH(2)-terminal kinase and caspase-3. Circulation. 101:2618–2624. 2000. View Article : Google Scholar : PubMed/NCBI
56	Liu J, Wu Y, Wang B, Yuan X and Fang B: High levels of glucose induced the caspase-3/PARP signaling pathway, leading to apoptosis in human periodontal ligament Fibroblasts. Cell Biochem Biophys. 66:229–237. 2013. View Article : Google Scholar : PubMed/NCBI
57	Yang LL, Liu JQ, Bai XZ, Fan L, Han F, Jia WB, Su LL, Shi JH, Tang CW and Hu DH: Acute downregulation of miR-155 at wound sites leads to a reduced fibrosis through attenuating inflammatory response. Biochem Biophys Res Commun. 453:153–159. 2014. View Article : Google Scholar : PubMed/NCBI