Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

Xu,Wenming; Wu,Wen; Chen,Jingfu; Guo,Runmin; Lin,Jiancong; Liao,Xinxue; Feng,Jianqiang

doi:10.3892/ijmm.2013.1462

October 2013 Volume 32 Issue 4

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October 2013 Volume 32 Issue 4

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Article

Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

Authors:
- Wenming Xu
- Wen Wu
- Jingfu Chen
- Runmin Guo
- Jiancong Lin
- Xinxue Liao
- Jianqiang Feng
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Affiliations: Department of Internal Medicine, Huangpu Division of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China, Department of Endocrinology, Guangdong Geriatrics Institute, Guangdong General Hospital, Guangzhou, Guangdong, P.R. China, Department of Cardiovasology, The Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong, P.R. China, Department of Cardiovasology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China, Department of Physiology, Zhongshan School of Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
Pages: 917-925
|
Published online on: August 1, 2013

https://doi.org/10.3892/ijmm.2013.1462
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Abstract

Hyperglycemia is a risk factor for the development of diabetic cardiovascular complications, which are associated with the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we demonstrate the inhibitory effects of exogenous hydrogen sulfide (H2S) on the activation of the MAPK pathway. The aim of the present study was to determine whether exogenous H2S prevents high glucose (HG)-induced injury by inhibiting the activation of the p38 MAPK and extracellular signal-regulated kinase (ERK)1/2 (members of MAPK) pathways in cardiomyoblasts (H9c2 cells). The findings of the present study demonstrated that the treatment of H9c2 cells with HG (35 mM glucose) for 24 h not only significantly induced injury, including cytotoxicity, apoptosis, overproduction of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (MMP), but also upregulated the expression levels of phosphorylated (p)-p38 MAPK and p-ERK1/2. The increased expression levels of p-p38 MAPK and p-ERK1/2 were markedly reduced by pre-treatment of the H9c2 cells with 400 µM sodium hydrogen sulfide (NaHS; a donor of H2S) prior to exposure to 35 mM glucose. Importantly, pre-treatment of the cells with 400 µM NaHS or 3 µM SB203580 (a selective inhibitor of p38 MAPK) or 15 µM U0126 (a selective inhibitor of ERK1/2) attenuated the HG-induced cardiomyocyte injury, leading to an increase in cell viability and a decrease in the number of apoptotic cells, preventing ROS generation, as well as the loss of MMP. In addition, pre-treatment of the cells with 1,000 µM N‑acetyl‑L‑cysteine (a ROS scavenger) prior to exposure to HG ameliorated the HG-induced cytotoxicity. Taken together, the data from the present study demonstrate for the first time, to our knowledge, that exogenous H2S exerts a protective effect against HG‑induced injury by inhibiting the activation of the p38 MAPK and ERK1/2 pathways and preventing oxidative stress in H9c2 cells.

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1	Grundy SM, Benjamin IJ, Burke GL, et al: Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 100:1134–1146. 1999. View Article : Google Scholar : PubMed/NCBI
2	Cai L and Kang YJ: Oxidative stress and diabetic cardiomyopathy: a brief review. Cardiovasc Toxicol. 1:181–193. 2001. View Article : Google Scholar : PubMed/NCBI
3	Francis GS: Diabetic cardiomyopathy: fact or fiction? Heart. 85:247–248. 2001. View Article : Google Scholar : PubMed/NCBI
4	Rodrigues B, Cam MC and McNeill JH: Metabolic disturbances in diabetic cardiomyopathy. Mol Cell Biochem. 180:53–57. 1998. View Article : Google Scholar : PubMed/NCBI
5	Privratsky JR, Wold LE, Sowers JR, Quinn MT and Ren J: AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase. Hypertension. 42:206–212. 2003. View Article : Google Scholar : PubMed/NCBI
6	Ren J and Davidoff AJ: Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes. Am J Physiol. 272:H148–H158. 1997.PubMed/NCBI
7	Rahimi R, Nikfar S, Larijani B and Abdollahi M: A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother. 59:365–373. 2005. View Article : Google Scholar : PubMed/NCBI
8	Cai H and Harrison DG: Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 87:840–844. 2000. View Article : Google Scholar : PubMed/NCBI
9	Peake BF, Nicholson CK, Lambert JP, et al: Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner. Am J Physiol Heart Circ Physiol. 304:H1215–H1224. 2013. View Article : Google Scholar
10	Soetikno V, Sari FR, Sukumaran V, et al: Curcumin prevents diabetic cardiomyopathy in streptozotocin-induced diabetic rats: possible involvement of PKC-MAPK signaling pathway. Eur J Pharm Sci. 47:604–614. 2012. View Article : Google Scholar : PubMed/NCBI
11	Evans JL, Goldfine ID, Maddux BA and Grodsky GM: Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev. 23:599–622. 2002. View Article : Google Scholar : PubMed/NCBI
12	Igarashi M, Wakasaki H, Takahara N, et al: Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest. 103:185–195. 1999. View Article : Google Scholar : PubMed/NCBI
13	Yan J, Young ME, Cui L, Lopaschuk GD, Liao R and Tian R: Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity. Circulation. 119:2818–2828. 2009. View Article : Google Scholar
14	Fang S, Jin Y, Zheng H, et al: High glucose condition upregulated Txnip expression level in rat mesangial cells through ROS/MEK/MAPK pathway. Mol Cell Biochem. 347:175–182. 2011. View Article : Google Scholar : PubMed/NCBI
15	Łowicka E and Bełtowski J: Hydrogen sulfide (H₂S) - the third gas of interest for pharmacologists. Pharmacol Rep. 59:4–24. 2007.
16	Moore PK, Bhatia M and Moochhala S: Hydrogen sulfide: from the smell of the past to the mediator of the future? Trends Pharmacol Sci. 24:609–611. 2003. View Article : Google Scholar : PubMed/NCBI
17	Geng B, Chang L, Pan C, et al: Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem Biophys Res Commun. 318:756–763. 2004. View Article : Google Scholar : PubMed/NCBI
18	Calvert JW, Jha S, Gundewar S, et al: Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res. 105:365–374. 2009. View Article : Google Scholar : PubMed/NCBI
19	Chen SL, Yang CT, Yang ZL, et al: Hydrogen sulphide protects H9c2 cells against chemical hypoxia-induced injury. Clin Exp Pharmacol Physiol. 37:316–321. 2010. View Article : Google Scholar : PubMed/NCBI
20	Yang Z, Yang C, Xiao L, et al: Novel insights into the role of HSP90 in cytoprotection of H₂S against chemical hypoxia-induced injury in H9c2 cardiac myocytes. Int J Mol Med. 28:397–403. 2011.PubMed/NCBI
21	Nicholson CK and Calvert JW: Hydrogen sulfide and ischemia-reperfusion injury. Pharmacol Res. 62:289–297. 2010. View Article : Google Scholar : PubMed/NCBI
22	Lan A, Liao X, Mo L, et al: Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells. PLoS One. 6:e259212011. View Article : Google Scholar : PubMed/NCBI
23	Dong XB, Yang CT, Zheng DD, et al: Inhibition of ROS-activated ERK1/2 pathway contributes to the protection of H₂S against chemical hypoxia-induced injury in H9c2 cells. Mol Cell Biochem. 362:149–157. 2012. View Article : Google Scholar : PubMed/NCBI
24	Suzuki K, Olah G, Modis K, et al: Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function. Proc Natl Acad Sci USA. 108:13829–13834. 2011. View Article : Google Scholar
25	Malhotra A, Vashistha H, Yadav VS, et al: Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis. Am J Physiol Heart Circ Physiol. 296:H380–H388. 2009. View Article : Google Scholar
26	Yuan Z, Feng W, Hong J, Zheng Q, Shuai J and Ge Y: p38MAPK and ERK promote nitric oxide production in cultured human retinal pigmented epithelial cells induced by high concentration glucose. Nitric Oxide. 20:9–15. 2009. View Article : Google Scholar
27	Wilmer WA, Dixon CL and Hebert C: Chronic exposure of human mesangial cells to high glucose environments activates the p38 MAPK pathway. Kidney Int. 60:858–871. 2001. View Article : Google Scholar : PubMed/NCBI
28	Sugden PH and Clerk A: ‘Stress-responsive’ mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res. 83:345–352. 1998.
29	Guo R, Lin J, Xu W, et al: Hydrogen sulfide attenuates doxorubicin-induced cardiotoxicity by inhibition of the p38 MAPK pathway in H9c2 cells. Int J Mol Med. 31:644–650. 2013.PubMed/NCBI
30	Yang J, Liu X, Bhalla K, et al: Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 275:1129–1132. 1997. View Article : Google Scholar : PubMed/NCBI
31	Yue TL, Wang C, Gu JL, et al: Inhibition of extracellular signal-regulated kinase enhances Ischemia/Reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ Res. 86:692–699. 2000. View Article : Google Scholar
32	Strohm C, Barancik T, Brühl ML, Kilian SA and Schaper W: Inhibition of the ER-kinase cascade by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium. J Cardiovasc Pharmacol. 36:218–229. 2000. View Article : Google Scholar : PubMed/NCBI
33	Buehler A, Martire A, Strohm C, et al: Angiogenesis-independent cardioprotection in FGF-1 transgenic mice. Cardiovasc Res. 55:768–777. 2002. View Article : Google Scholar : PubMed/NCBI
34	Chen L, Liu L, Yin J, Luo Y and Huang S: Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. Int J Biochem Cell Biol. 41:1284–1295. 2009. View Article : Google Scholar : PubMed/NCBI
35	Jain SK, Bull R, Rains JL, et al: Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signal. 12:1333–1337. 2010. View Article : Google Scholar : PubMed/NCBI
36	Yusuf M, Kwong Huat BT, Hsu A, Whiteman M, Bhatia M and Moore PK: Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis. Biochem Biophys Res Commun. 333:1146–1152. 2005. View Article : Google Scholar : PubMed/NCBI
37	Ahmad FU, Sattar MA, Rathore HA, et al: Exogenous hydrogen sulfide (H₂S) reduces blood pressure and prevents the progression of diabetic nephropathy in spontaneously hypertensive rats. Ren Fail. 34:203–210. 2012.PubMed/NCBI
38	Whiteman M, Gooding KM, Whatmore JL, et al: Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia. 53:1722–1726. 2010. View Article : Google Scholar : PubMed/NCBI
39	Gao Y, Yao X, Zhang Y, et al: The protective role of hydrogen sulfide in myocardial ischemia-reperfusion-induced injury in diabetic rats. Int J Cardiol. 152:177–183. 2011. View Article : Google Scholar : PubMed/NCBI
40	Hu LF, Wong PT, Moore PK and Bian JS: Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia. J Neurochem. 100:1121–1128. 2007. View Article : Google Scholar
41	Hu LF, Lu M, Wu ZY, Wong PT and Bian JS: Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function. Mol Pharmacol. 75:27–34. 2009. View Article : Google Scholar : PubMed/NCBI
42	Adhikari S and Bhatia M: H₂S-induced pancreatic acinar cell apoptosis is mediated via JNK and p38 MAP kinase. J Cell Mol Med. 12:1374–1383. 2008.
43	Zhi L, Ang AD, Zhang H, Moore PK and Bhatia M: Hydrogen sulfide induces the synthesis of proinflammatory cytokines in human monocyte cell line U937 via the ERK-NF-kappaB pathway. J Leukoc Biol. 81:1322–1332. 2007. View Article : Google Scholar : PubMed/NCBI
44	Mukherjee S, Lekli I, Goswami S and Das DK: Freshly crushed garlic is a superior cardioprotective agent than processed garlic. J Agric Food Chem. 57:7137–7144. 2009. View Article : Google Scholar : PubMed/NCBI
45	Hu Y, Chen X, Pan TT, et al: Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways. Pflugers Arch. 455:607–616. 2008. View Article : Google Scholar : PubMed/NCBI
46	Yang G, Wu L, Bryan S, Khaper N, Mani S and Wang R: Cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells. Cardiovasc Res. 86:487–495. 2010. View Article : Google Scholar : PubMed/NCBI
47	Yang G, Yang W, Wu L and Wang R: H₂S, endoplasmic reticulum stress, and apoptosis of insulin-secreting beta cells. J Biol Chem. 282:16567–16576. 2007.PubMed/NCBI
48	Lu M, Hu LF, Hu G and Bian JS: Hydrogen sulfide protects astrocytes against H(2)O(2)-induced neural injury via enhancing glutamate uptake. Free Radic Biol Med. 45:1705–1713. 2008. View Article : Google Scholar : PubMed/NCBI
49	Kloesch B, Liszt M and Broell J: H₂S transiently blocks IL-6 expression in rheumatoid arthritic fibroblast-like synoviocytes and deactivates p44/42 mitogen-activated protein kinase. Cell Biol Int. 34:477–484. 2010.
50	Cai WJ, Wang MJ, Moore PK, Jin HM, Yao T and Zhu YC: The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc Res. 76:29–40. 2007. View Article : Google Scholar : PubMed/NCBI
51	Bliksøen M, Kaljusto ML, Vaage J and Stensløkken KO: Effects of hydrogen sulphide on ischaemia-reperfusion injury and ischaemic preconditioning in the isolated, perfused rat heart. Eur J Cardiothorac Surg. 34:344–349. 2008.PubMed/NCBI
52	Marshall CJ: Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 80:179–185. 1995. View Article : Google Scholar

Journals

International Journal of Molecular Medicine

International Journal of Oncology

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Medicine International

Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

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