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Metformin protects against hyperglycemia-induced cardiomyocytes injury by inhibiting the expressions of receptor for advanced glycation end products and high mobility group box 1 protein

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Abstract

Metformin (MET), an anti-diabetic oral drug with antioxidant properties, has been proved to provide cardioprotective effects in patients with diabetic disease. However, the mechanism is unclear. This study aimd to investigate the effects of MET on the expressions of receptor for advanced glycation end products (RAGE) and high mobility group box 1 protein (HMGB1) in hyperglycemia-treated neonatal rat ventricular myocytes. Cardiocytes were prepared and cultured with high glucose and different concentrations of MET. The expressions of RAGE and HMGB1 were evaluated by Western blot analysis. The superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), lactate dehydrogenase (LDH) and creatine kinase (CK) were measured. After 12 h-incubation, MET significantly inhibited the increase of MDA, TNF-α, LDH and CK levels induced by high glucose, especially at the 5 × 10−5 to 10−4 mol/L concentrations while inhibiting the decrease of SOD level. Meanwhile, RAGE and HMGB1 expression were significantly increased induced by hyperglycaemia for 24 h (P < 0.05). MET inhibited the expressions of RAGE and HMGB1 in a dose-dependent manner, especially at the 5 × 10−5 to 10−4 mol/L concentrations (P < 0.05). In conclusion, our study suggested that MET could reduce hyperglycemia-induced cardiocytes injury by inhibiting the expressions of RAGE and HMGB1.

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Abbreviations

MET:

Metformin

HMGB1:

High mobility group box 1 protein

RAGE:

Receptor for advanced glycation end products

TNF-α:

Tumor necrosis factor-α

MDA:

Malondialdehyde

SOD:

Superoxide dismutase

LDH:

Lactate dehydrogenase

CK:

Creatine kinase

References

  1. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan WC, Elliston K, Stern D, Shaw A (1992) Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267:14998–15004

    CAS  PubMed  Google Scholar 

  2. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195

    Article  CAS  PubMed  Google Scholar 

  3. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Portro A, Bachi A, Rubartelli A, Aqresti A, Bianchi ME (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBOJ 22:5551–5560

    Article  CAS  Google Scholar 

  4. Agnello D, Wang H, Yang H, Tracey KJ, Ghezzi P (2002) HMGB-1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. Cytokine 18:231–236

    Article  CAS  PubMed  Google Scholar 

  5. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, Czura CJ, Wang H, Roth J, Warren HS, Fink MP, Fenton MJ, Andersson U, Tracey KJ (2004) Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 101:296–301

    Article  CAS  PubMed  Google Scholar 

  6. Volz HC, Seidel C, Laohachewin D, Kaya Z, Müller OJ, Pleger ST, Lasitschka F, Bianchi ME, Remppis A, Bierhaus A, Katus HA, Andrassy M (2010) HMGB1: the missing link between diabetes mellitus and heart failure. Basic Res Cardiol 105:805–820

    Article  CAS  PubMed  Google Scholar 

  7. Hu X, Jiang H, Bai Q, Zhou X, Xu C, Lu Z, Cui B, Wen H (2009) Increased serum HMGB1 is related to the severity of coronary artery stenosis. Clin Chim Acta 406:139–142

    Article  CAS  PubMed  Google Scholar 

  8. Hu X, Zhou X, He B, Xu C, Wu L, Cui B, Wen H, Lu Z, Jiang H (2010) Minocycline protects against myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. Eur J Pharmacol 638:84–89

    Article  CAS  PubMed  Google Scholar 

  9. Hu X, Zhou W, Bai Q, Wang J, Yang X, Xu C, Jing H (2011) Increased serum high mobility group box 1 protein in patients with atrial fibrillation. Biomed Aging Pathol 1:52–55

    Article  Google Scholar 

  10. Abbasi F, Chu JW, McLaughlin T, Lamendola C, Leary ET, Reaven GM (2004) Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus. Metabolism 53:159–164

    Article  CAS  PubMed  Google Scholar 

  11. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). Lancet 352:854–865

    Article  Google Scholar 

  12. Bonnefont-Rousselot D, Raji B, Walrand S, Gardès-Albert M, Jore D, Legrand A, Peynet J, Vasson MP (2003) An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. Metabolism 52:586–589

    Article  CAS  PubMed  Google Scholar 

  13. Ouslimani N, Mahrouf M, Peynet J, Bonnefont-Rousselot D, Cosson C, Legrand A, Beaudeux JL (2007) Metformin reduces endothelial cell expression of both the receptor for advanced glycation end products and lectin-like oxidized receptor 1. Metabolism 56:308–313

    Article  CAS  PubMed  Google Scholar 

  14. Hou X, Song J, Li XN, Zhang L, Wang X, Chen L, Shen YH (2010) Metformin reduces intracellular reactive oxygen species levels by up regulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun 396:199–205

    Article  CAS  PubMed  Google Scholar 

  15. Tsoyi K, Jang HJ, Nizamutdinova IT, Kim YM, Lee YS, Kim HJ, Seo HG, Lee JH, Chang KC (2011) Metformin inhibits HMGB1 release in LPS-treated RAW264.7cells and increases survival rate of endotoxaemic mice. Br J Pharmacol 162:1498–1508

    Article  CAS  PubMed  Google Scholar 

  16. Yan L, Tang Q, Shen D, Peng S, Zheng Q, Guo H, Jiang M, Deng W (2008) SOCS-1 inhibits TNF-alpha-induced cardiomyocyte apoptosis via ERK1/2 pathway activation. Inflammation 31:180–188

    Article  CAS  PubMed  Google Scholar 

  17. Cai Y, Hu X, Yi B, Zhang T, Wen Z (2012) Glucagon-like peptide-1 protects against hyperglycemia-induced cardiomyocytes injury by inhibiting high group box 1 expression. Mol Biol Rep 39:10705–10711

    Article  CAS  PubMed  Google Scholar 

  18. Hu X, Cui B, Zhou X, Xu C, Lu Z, Jiang H (2012) Ethyl pyruvate reduces myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. Mol Biol Rep 39:227–231

    Article  CAS  PubMed  Google Scholar 

  19. Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, Buss S, Autschbach F, Pleger ST, Lukic IK, Bea F, Hardt SE, Humpert PM, Bianchi ME, Mairbäurl H, Nawroth PP, Remppis A, Katus HA, Bierhaus A (2008) High-mobility group box-1 in ischemia–reperfusion injury of the heart. Circulation 117:3216–3226

    Article  CAS  PubMed  Google Scholar 

  20. Andrassy M, Volz HC, Bianchi ME (2008) The role of Hmgb1 in the development of diabetic cardiomyopathy. Circulation 118:S351–S352

    Google Scholar 

  21. Bell CW, Jiang W, Reich CF 3rd, Pisetsky DS (2006) The extracellular release of HMGB1 during apoptotic cell death. Am J Physiol Cell Physiol 291:C1318–C1325

    Article  CAS  PubMed  Google Scholar 

  22. Xu H, Su Z, Wu J, Yang M, Penninger JM, Martin CM, Kvietys PR, Rui T (2010) The alarmin cytokine, high mobility group box 1, is produced by viable cardiomyocytes and mediates the lipo polysaccharide-induced myocardial dysfunction via a TLR4/phosphatidy linositol 3-kinase γ pathway. J Immunol 184:1492–1498

    Article  CAS  PubMed  Google Scholar 

  23. Nath N, Khan M, Paintlia MK, Singh I, Hoda MN, Giri S (2009) Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol 182:8005–8014

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Tan BK, Adya R, Chen J, Farhatullah S, Heutling D, Mitchell D, Lehnert H, Randeva HS (2009) Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovasc Res 83:566–574

    Article  CAS  PubMed  Google Scholar 

  25. Gonzalez-Angulo AM, Meric-Bernstam F (2010) Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res 16:1695–1700

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ouslimani N, Peynet J, Bonnefont-Rousselot D, Thérond P, Legrand A, Beaudeux JL (2005) Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. Metabolism 54:829–834

    Article  CAS  PubMed  Google Scholar 

  27. Kalinina N, Aqrotis A, Antropova Y, DiVitto G, Kanellakis P, Kostolias G, Ilyinskaya O, Tararak E, Bobik A (2004) Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions: role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol 24:2320–2325

    Article  CAS  PubMed  Google Scholar 

  28. Alhaider AA, Korashy HM, Sayed-Anmed MM, Mobark M, Kfoury H, Mansour MA (2011) Metformin attenuates streptozotocin-induced diabetic nephropathy in rats through modulation of oxidative stress genes expression. Chem Biol Interact 192:233–242

    Article  CAS  PubMed  Google Scholar 

  29. Fidan E, Onder Ersoz H, Yilmaz M, Yilmaz H, Kocak M, Karahan C, Erem C (2011) The effects of rosiglitazone and metformin on inflammation and endothelial dysfunction in patients with type 2 diabetes mellitus. Acta Diabetol 48:297–302

    Article  CAS  PubMed  Google Scholar 

  30. Wang XF, Zhang JY, Li L, Zhao XY, Tao HL, Zhang L (2011) Metformin improves cardiac function in rats via activation of AMP-activated protein kinase. Clin Exp Pharmacol Physiol 38:94–101

    Article  PubMed  Google Scholar 

  31. Yao D, Brownlee M (2010) Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes 59:249–255

    Article  CAS  PubMed  Google Scholar 

  32. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage. Nature 404:787–790

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was partially supported by a grant from National Natural Science foundation of China (No. 81100146 and 81370308), Grant 111023 from the Fundamental Research Funds for the Central Universities and the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20110141120060), and the Fundamental Research Funds of Wuhan City (No. 2013070104010044).

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Authors and Affiliations

  1. Department of Endocrinology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060, China

    Ting Zhang, Yuli Cai, Bo Yi & Zhongyuan Wen

  2. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    Xiaorong Hu

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  1. Ting Zhang
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Correspondence to Zhongyuan Wen.

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Zhang, T., Hu, X., Cai, Y. et al. Metformin protects against hyperglycemia-induced cardiomyocytes injury by inhibiting the expressions of receptor for advanced glycation end products and high mobility group box 1 protein. Mol Biol Rep 41, 1335–1340 (2014). https://doi.org/10.1007/s11033-013-2979-3

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