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GYY4137, a novel hydrogen sulfide-releasing molecule, likely protects against high glucose-induced cytotoxicity by activation of the AMPK/mTOR signal pathway in H9c2 cells

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Abstract

Diabetic cardiomyopathy (DCM) has become a major cause of diabetes-related morbidity and mortality. Increasing evidences have proved that hydrogen sulfide (H2S) fulfills a positive role in regulating diabetic myocardial injury. The present study was designed to determine whether GYY4137, a novel H2S-releasing molecule, protected H9c2 cells against high glucose (HG)-induced cytotoxicity by activation of the AMPK/mTOR signal pathway. H9c2 cells were incubated in normal glucose (5.5 mM), 22, 33, and 44 mM glucose for 24 h to mimic the hyperglycemia in DCM in vitro. Then we added 50, 100, and 200 μM GYY4137, and measured the cell viability, lactate dehydrogenase (LDH) enzyme activity, and mitochondrial membrane potential (MMP). 0.5 mM 5-amino-4-imidazole-carboxamide riboside (AICAR, an AMPK activator) and 1 mM adenine 9-β-d-arabinofuranoside (Ara-A, an AMPK inhibitor) were used to identity whether the AMPK/mTOR signal pathway was involved in GYY4137-mediated cardioprotection. We demonstrated that HG decreased cell viability and increased LDH enzyme activity in a concentration-dependent manner. 33 mM HG treatment for 24 h was chosen as our model group for further study. Both 100 and 200 μM GYY4137 treatments significantly attenuated HG-induced cell viability decrement, LDH enzyme activity increase, and MMP collapse. AICAR had similar effects to GYY4137 treatment while Ara-A attenuated GYY4137-mediated cardioprotection. Importantly, both GYY4137 and AICAR increased AMPK phosphorylation and decreased mTOR phosphorylation compared with the HG model group while Ara-A attenuated GYY4137-mediated AMPK phosphorylation increase and mTOR phosphorylation decrement. In conclusion, we propose that GYY4137 likely protects against HG-induced cytotoxicity by activation of the AMPK/mTOR signal pathway in H9c2 cells.

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Abbreviations

DCM:

Diabetic cardiomyopathy

H2S:

Hydrogen sulfide

HG:

High glucose

LDH:

Lactate dehydrogenase

MMP:

Mitochondrial membrane potential

AICAR:

5-Amino-4-imidazole-carboxamide riboside

Ara-A:

Adenine 9-β-d-arabinofuranoside

References

  1. Chen L, Magliano DJ, Zimmet PZ (2012) The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat Rev Endocrinol 8(4):228–236

    Article  CAS  Google Scholar 

  2. Battiprolu PK, Lopez-Crisosto C, Wang ZV, Nemchenko A, Lavandero S, Hill JA (2013) Diabetic cardiomyopathy and metabolic remodeling of the heart. Life Sci 92(11):609–615

    Article  CAS  PubMed  Google Scholar 

  3. Goyal BR, Mehta AA (2013) Diabetic cardiomyopathy: pathophysiological mechanisms and cardiac dysfunction. Hum Exp Toxicol 32(6):571–590

    Article  CAS  PubMed  Google Scholar 

  4. Falcao-Pires I, Leite-Moreira AF (2012) Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev 17(3):325–344

    Article  CAS  PubMed  Google Scholar 

  5. Hwang SL, Jeong YT, Hye YJ, Li X, Lu Y, Son JK, Chang HW (2013) Pinusolide improves high glucose-induced insulin resistance via activation of AMP-activated protein kinase. Biochem Biophys Res Commun 437(3):374–379

    Article  CAS  PubMed  Google Scholar 

  6. Perna AF, Luciano MG, Ingrosso D, Raiola I, Pulzella P, Sepe I, Lanza D, Violetti E, Capasso R, Lombardi C, De Santo NG (2010) Hydrogen sulfide, the third gaseous signaling molecule with cardiovascular properties, is decreased in hemodialysis patients. J Ren Nutr 20(5 Suppl):S11–S14

    Article  CAS  PubMed  Google Scholar 

  7. Blackstone E, Morrison M, Roth MB (2005) H2S induces a suspended animation-like state in mice. Science 308(5721):518

    Article  CAS  PubMed  Google Scholar 

  8. Kashfi K, Olson KR (2013) Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras. Biochem Pharmacol 85(5):689–703

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Zhou X, Lu X (2013) Hydrogen sulfide inhibits high-glucose-induced apoptosis in neonatal rat cardiomyocytes. Exp Biol Med (Maywood) 238(4):370–374

    Article  Google Scholar 

  10. Peake BF, Nicholson CK, Lambert JP, Hood RL, Amin H, Amin S, Calvert JW (2013) 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(9):H1215–H1224

    Article  CAS  PubMed  Google Scholar 

  11. Li L, Whiteman M, Guan YY, Neo KL, Cheng Y, Lee SW, Zhao Y, Baskar R, Tan CH, Moore PK (2008) Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 117(18):2351–2360

    Article  CAS  PubMed  Google Scholar 

  12. Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8(10):774–785

    Article  CAS  PubMed  Google Scholar 

  13. Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y (2010) AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab 298(4):E751–E760

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X (2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 9(4):327–338

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Mantovani J, Roy R (2011) Re-evaluating the general(ized) roles of AMPK in cellular metabolism. FEBS Lett 585(7):967–972

    Article  CAS  PubMed  Google Scholar 

  16. Liao LZ, Chen YL, Lu LH, Zhao YH, Guo HL, Wu WK (2013) Polysaccharide from Fuzi likely protects against starvation-induced cytotoxicity in H9c2 cells by increasing autophagy through activation of the AMPK/mTOR pathway. Am J Chin Med 41(2):353–367

    Article  CAS  PubMed  Google Scholar 

  17. Bian S, Sun X, Bai A, Zhang C, Li L, Enjyoji K, Junger WG, Robson SC, Wu Y (2013) P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS One 8(4):e60184

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Dyck JR, Lopaschuk GD (2006) AMPK alterations in cardiac physiology and pathology: enemy or ally? J Physiol 574(Pt 1):95–112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Chen BL, Ma YD, Meng RS, Xiong ZJ, Wang HN, Zeng JY, Liu C, Dong YG (2010) Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro. Acta Pharmacol Sin 31(7):798–804

    Article  CAS  PubMed  Google Scholar 

  20. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100(6):914–922

    Article  CAS  PubMed  Google Scholar 

  21. Jain SK, Manna P, Micinski D, Lieblong BJ, Kahlon G, Morehead L, Hoeldtke R, Bass PR, Levine SN (2013) In African American type 2 diabetic patients, is vitamin D deficiency associated with lower blood levels of hydrogen sulfide and cyclic adenosine monophosphate, and elevated oxidative stress? Antioxid Redox Signal 18(10):1154–1158

    Article  CAS  PubMed  Google Scholar 

  22. Brancaleone V, Roviezzo F, Vellecco V, De Gruttola L, Bucci M, Cirino G (2008) Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice. Br J Pharmacol 155(5):673–680

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Zhong X, Wang L, Wang Y, Dong S, Leng X, Jia J, Zhao Y, Li H, Zhang X, Xu C, Yang G, Wu L, Wang R, Lu F, Zhang W (2012) Exogenous hydrogen sulfide attenuates diabetic myocardial injury through cardiac mitochondrial protection. Mol Cell Biochem 371(1–2):187–198

    Article  CAS  PubMed  Google Scholar 

  24. Xue R, Hao DD, Sun JP, Li WW, Zhao MM, Li XH, Chen Y, Zhu JH, Ding YJ, Liu J, Zhu YC (2013) Hydrogen sulfide treatment promotes glucose uptake by increasing insulin receptor sensitivity and ameliorates kidney lesions in type 2 diabetes. Antioxid Redox Signal 19(1):5–23

    Article  CAS  PubMed  Google Scholar 

  25. Zhang X, Chen C (2012) A new insight of mechanisms, diagnosis and treatment of diabetic cardiomyopathy. Endocrine 41(3):398–409

    Article  CAS  PubMed  Google Scholar 

  26. Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115(25):3213–3223

    Article  PubMed  Google Scholar 

  27. Aurigemma GP, de Simone G, Fitzgibbons TP (2013) Cardiac remodeling in obesity. Circ Cardiovasc Imaging 6(1):142–152

    Article  PubMed  Google Scholar 

  28. Bugger H, Abel ED (2008) Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clin Sci (Lond) 114(3):195–210

    Article  CAS  Google Scholar 

  29. Akbal E, Ozbek M, Gunes F, Akyurek O, Ureten K, Delibasi T (2009) Serum heart type fatty acid binding protein levels in metabolic syndrome. Endocrine 36(3):433–437

    Article  CAS  PubMed  Google Scholar 

  30. Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED (2005) Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146(12):5341–5349

    Article  CAS  PubMed  Google Scholar 

  31. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, Dence C, Klein S, Marsala J, Meyer T, Gropler RJ (2004) Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109(18):2191–2196

    Article  PubMed  Google Scholar 

  32. Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1(1):15–25

    Article  CAS  PubMed  Google Scholar 

  33. Kim MY, Lim JH, Youn HH, Hong YA, Yang KS, Park HS, Chung S, Ko SH, Shin SJ, Choi BS, Kim HW, Kim YS, Lee JH, Chang YS, Park CW (2013) Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1alpha axis in db/db mice. Diabetologia 56(1):204–217

    Article  CAS  PubMed  Google Scholar 

  34. Zou MH, Xie Z (2013) Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK. Autophagy 9(4):624–625

    Article  CAS  PubMed  Google Scholar 

  35. Lee HJ, Mariappan MM, Feliers D, Cavaglieri RC, Sataranatarajan K, Abboud HE, Choudhury GG, Kasinath BS (2012) Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMP-activated protein kinase in renal epithelial cells. J Biol Chem 287(7):4451–4461

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This study was supported by National Nature Science Foundation of China (Grant No. 81270296) and Science and Technology Planning Project of Guangdong Province in China (2010B080701105).

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Authors and Affiliations

  1. Department of Cardiovascular, the Fourth People’s Hospital of Shenzhen, Shenzhen, 518033, People’s Republic of China

    Wen-bin Wei

  2. Department of Cardiovasology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China

    Xun Hu & Xiao-dong Zhuang

  3. Department of Health, Guangzhou Higher Education Mega Center, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China

    Li-zhen Liao & Wei-dong Li

Authors
  1. Wen-bin Wei
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  2. Xun Hu
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  3. Xiao-dong Zhuang
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  4. Li-zhen Liao
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  5. Wei-dong Li
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Corresponding authors

Correspondence to Li-zhen Liao or Wei-dong Li.

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Wen-bin Wei and Xun Hu have contributed equally to this work.

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Wei, Wb., Hu, X., Zhuang, Xd. et al. GYY4137, a novel hydrogen sulfide-releasing molecule, likely protects against high glucose-induced cytotoxicity by activation of the AMPK/mTOR signal pathway in H9c2 cells. Mol Cell Biochem 389, 249–256 (2014). https://doi.org/10.1007/s11010-013-1946-6

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