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Metformin alleviates monoamine oxidase-related vascular oxidative stress and endothelial dysfunction in rats with diet-induced obesity

Abstract

In the past decade, monoamine oxidase (MAO) with 2 isoforms, MAO-A and B, has emerged as an important source of mitochondrial reactive oxygen species (ROS) in cardio-metabolic pathologies. We have previously reported that MAO-related oxidative stress mediates endothelial dysfunction in rodent models of diabetes and diabetic patients; however, the role of MAO in the vascular impairment associated to obesity has not been investigated so far. Metformin (METF), the first-line drug in the therapy of type 2 diabetes mellitus, has been reported to elicit vasculoprotective effects via partially elucidated mechanisms. The present study was purported to assess the effects of METF on MAO expression, ROS production and vasomotor function of aortas isolated from rats with diet-induced obesity. After 24 weeks of high calorie junk food (HCJF) diet, isolated aortic rings were prepared and treated with METF (10 μM, 12 h incubation). Measurements of MAO expression (quantitative PCR and immune histochemistry), ROS production (spectrometry and immune-fluorescence) and vascular reactivity (myograph studies) were performed in rat aortic rings. MAO expression was upregulated in aortic rings isolated from obese rats together with an increase in ROS production and an impairment of vascular reactivity. METF decreased MAO expression and ROS generation, reduced vascular contractility and improved the endothelium-dependent relaxation in the diseased vascular preparations. In conclusion, METF elicited vascular protective effects via the mitigation of MAO-related oxidative stress in the rat model of diet-induced obesity.

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References

  1. Blendea MC, McFarlane SI, Isenovic ER, Gick G, Sowers JR (2003) Heart disease in diabetic patients. Curr Diab Rep 3:223–229. https://doi.org/10.1007/s11892-003-0068-z

    Article  PubMed  Google Scholar 

  2. Black CN, Penninx BW, Bot M, Odegaard AO, Gross MD, Matthews KA, Jacobs DR (2016) Oxidative stress, anti-oxidants and the cross-sectional and longitudinal association with depressive symptoms: results from the CARDIA study. Transl Psychiatry 6:e743. https://doi.org/10.1038/tp.2016.5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Savoiu Balint GBC, Cristescu C, Andoni M, Simu GM, Malita D, Malita I, Cheveresan A (2011) Endogenous and exogenous antioxidant protection for endothelial dysfunction. Revista de Chimie (Rev. Chim.) 62:680–683

    Google Scholar 

  4. Chen Q, Wang Q, Zhu J, Xiao Q, Zhang L (2018) Reactive oxygen species: key regulators in vascular health and diseases. Br J Pharmacol 175:1279–1292. https://doi.org/10.1111/bph.13828

    CAS  Article  PubMed  Google Scholar 

  5. Sena CM, Leandro A, Azul L, Seiça R, Perry G (2018) Vascular oxidative stress: impact and therapeutic approaches. Front Physiol 9:1668. https://doi.org/10.3389/fphys.2018.01668

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sturza A, Popoiu CM, Ionică M, Duicu OM, Olariu S, Muntean DM, Boia ES (2019) Monoamine oxidase-related vascular oxidative stress in diseases associated with inflammatory burden. Oxid Med Cell Longev 2019:8954201. https://doi.org/10.1155/2019/8954201

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Youdim MBH (2018) Monoamine oxidase inhibitors, and iron chelators in depressive illness and neurodegenerative diseases. J Neural Transm (Vienna) 125:1719–1733. https://doi.org/10.1007/s00702-018-1942-9

    CAS  Article  Google Scholar 

  8. Di Lisa F, Kaludercic N, Carpi A, Menabò R, Giorgio M (2009) Mitochondria and vascular pathology. Pharmacol Rep 61:123–130. https://doi.org/10.1016/s1734-1140(09)70014-3

    Article  PubMed  Google Scholar 

  9. Lighezan R, Sturza A, Duicu OM, Ceausu RA, Vaduva A, Gaspar M, Feier H, Vaida M, Ivan V, Lighezan D, Muntean DM, Mornos C (2016) Monoamine oxidase inhibition improves vascular function in mammary arteries from nondiabetic and diabetic patients with coronary heart disease. Can J Physiol Pharmacol 94:1040–1047. https://doi.org/10.1139/cjpp-2015-0580

    CAS  Article  PubMed  Google Scholar 

  10. Sturza A, Duicu OM, Vaduva A, Dănilă MD, Noveanu L, Varró A, Muntean DM (2015) Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes. Can J Physiol Pharmacol 93:555–561. https://doi.org/10.1139/cjpp-2014-0544

    CAS  Article  PubMed  Google Scholar 

  11. Sturza A, Leisegang MS, Babelova A, Schroder K, Benkhoff S, Loot AE, Fleming I, Schulz R, Muntean DM, Brandes RP (2013) Monoamine oxidases are mediators of endothelial dysfunction in the mouse aorta. Hypertension 62:140–146. https://doi.org/10.1161/hypertensionaha.113.01314

    CAS  Article  PubMed  Google Scholar 

  12. World Health Organization. WHO model list of essential medicines. World Health Organization; 2011. http://www.who. int/medicines/publications/essentialmedicines/en/index.html. Accessed April 30.

  13. LaMoia TE, Shulman GI (2020) Cellular and molecular mechanisms of metformin action. Endocr Rev. https://doi.org/10.1210/endrev/bnaa023

    Article  PubMed Central  Google Scholar 

  14. Zilov AV, Abdelaziz SI, AlShammary A, Al Zahrani A, Amir A, Assaad Khalil SH, Brand K, Elkafrawy N, Hassoun AAK, Jahed A, Jarrah N, Mrabeti S, Paruk I (2019) Mechanisms of action of metformin with special reference to cardiovascular protection. Diabetes Metab Res Rev 35:e3173. https://doi.org/10.1002/dmrr.3173

    Article  PubMed  PubMed Central  Google Scholar 

  15. Nesti L, Natali A (2017) Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis 27:657–669. https://doi.org/10.1016/j.numecd.2017.04.009

    CAS  Article  PubMed  Google Scholar 

  16. Kinaan M, Ding H, Triggle CR (2015) Metformin: An old drug for the treatment of diabetes but a new drug for the protection of the endothelium. Med Princ Pract 24:401–415. https://doi.org/10.1159/000381643

    Article  PubMed  PubMed Central  Google Scholar 

  17. Manzella D, Grella R, Esposito K, Giugliano D, Barbagallo M, Paolisso G (2004) Blood pressure and cardiac autonomic nervous system in obese type 2 diabetic patients: effect of metformin administration. Am J Hypertens 17:223–227. https://doi.org/10.1016/j.amjhyper.2003.11.006

    CAS  Article  PubMed  Google Scholar 

  18. de Jager J, Kooy A, Schalkwijk C, van der Kolk J, Lehert P, Bets D, Wulffele MG, Donker AJ, Stehouwer CD (2014) Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. J Intern Med 275:59–70. https://doi.org/10.1111/joim.12128

    CAS  Article  PubMed  Google Scholar 

  19. Wulffele MG, Kooy A, Lehert P, Bets D, Donker AJ, Stehouwer CD (2005) Does metformin decrease blood pressure in patients with Type 2 diabetes intensively treated with insulin? Diabet Med 22:907–913. https://doi.org/10.1111/j.1464-5491.2005.01554.x

    CAS  Article  PubMed  Google Scholar 

  20. de Aguiar LG, Bahia LR, Villela N, Laflor C, Sicuro F, Wiernsperger N, Bottino D, Bouskela E (2006) Metformin improves endothelial vascular reactivity in first-degree relatives of type 2 diabetic patients with metabolic syndrome and normal glucose tolerance. Diabetes Care 29:1083–1089. https://doi.org/10.2337/diacare.2951083

    Article  PubMed  Google Scholar 

  21. Zhou JY, Poudel A, Welchko R, Mekala N, Chandramani-Shivalingappa P, Rosca MG, Li L (2019) Liraglutide improves insulin sensitivity in high fat diet induced diabetic mice through multiple pathways. Eur J Pharmacol 861:172594. https://doi.org/10.1016/j.ejphar.2019.172594

    CAS  Article  PubMed  Google Scholar 

  22. Sturza A, Duicu OM, Vaduva A, Danila MD, Noveanu L, Varro A, Muntean DM (2015) Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes. Can J Physiol Pharmacol. https://doi.org/10.1139/cjpp-2014-0544

    Article  PubMed  Google Scholar 

  23. Sturza A, Vaduva A, Utu D, Ratiu C, Pop N, Duicu O, Popoiu C, Boia E, Matusz P, Muntean DM, Olariu S (2018) Vitamin D improves vascular function and decreases monoamine oxidase A expression in experimental diabetes. Mol Cell Biochem. https://doi.org/10.1007/s11010-018-3429-2

    Article  PubMed  Google Scholar 

  24. Danila MD, Privistirescu A, Duicu OM, Ratiu CD, Angoulvant D, Muntean DM, Sturza A (2017) The effect of purinergic signaling via the P2Y11 receptor on vascular function in a rat model of acute inflammation. Mol Cell Biochem. https://doi.org/10.1007/s11010-017-2973-5

    Article  PubMed  Google Scholar 

  25. Duicu OM, Lighezan R, Sturza A, Balica R, Vaduva A, Feier H, Gaspar M, Ionac A, Noveanu L, Borza C, Muntean DM, Mornos C (2016) Assessment of Mitochondrial Dysfunction and Monoamine Oxidase Contribution to Oxidative Stress in Human Diabetic Hearts. Oxid Med Cell Longev 2016:8470394. https://doi.org/10.1155/2016/8470394

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Miller JD, Chu Y, Brooks RM, Richenbacher WE, Pena-Silva R, Heistad DD (2008) Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol 52:843–850. https://doi.org/10.1016/j.jacc.2008.05.043

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Brandes RP, Weissmann N, Schröder K (2010) NADPH oxidases in cardiovascular disease. Free Radic Biol Med 49:687–706. https://doi.org/10.1016/j.freeradbiomed.2010.04.030

    CAS  Article  PubMed  Google Scholar 

  28. Brandes RP, Weissmann N, Schröder K (2014) Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic Biol Med 76:208–226. https://doi.org/10.1016/j.freeradbiomed.2014.07.046

    CAS  Article  PubMed  Google Scholar 

  29. King P, Peacock I, Donnelly R (1999) The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol 48:643–648. https://doi.org/10.1046/j.1365-2125.1999.00092.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Griffin SJ, Leaver JK, Irving GJ (2017) Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 60:1620–1629. https://doi.org/10.1007/s00125-017-4337-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Zhou J, Massey S, Story D, Li L (2018) Metformin: An Old Drug with New Applications. Int J Mol Sci. https://doi.org/10.3390/ijms19102863

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ahmed FW, Bakhashab S, Bastaman IT, Crossland RE, Glanville M, Weaver JU (2018) Anti-Angiogenic miR-222, miR-195, and miR-21a Plasma Levels in T1DM Are Improved by Metformin Therapy, Thus Elucidating Its Cardioprotective Effect: The MERIT Study. Int J Mol Sci. https://doi.org/10.3390/ijms19103242

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dziubak A, Wójcicka G, Wojtak A, Bełtowski J (2018) Metabolic Effects of Metformin in the Failing Heart. Int J Mol Sci. https://doi.org/10.3390/ijms19102869

    Article  PubMed  PubMed Central  Google Scholar 

  34. Albai O, Timar B, Paun DL, Sima A, Roman D, Timar R (2020) Metformin Treatment: A Potential Cause of Megaloblastic Anemia in Patients with Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 13:3873–3878. https://doi.org/10.2147/dmso.s270393

    Article  PubMed  PubMed Central  Google Scholar 

  35. Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, McNeilly AD, Balfour DJ, Savinko T, Wong AK, Viollet B, Sakamoto K, Fagerholm SC, Foretz M, Lang CC, Rena G (2016) Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ Res 119:652–665. https://doi.org/10.1161/circresaha.116.308445

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Nafisa A, Gray SG, Cao Y, Wang T, Xu S, Wattoo FH, Barras M, Cohen N, Kamato D, Little PJ (2018) Endothelial function and dysfunction: Impact of metformin. Pharmacol Ther 192:150–162. https://doi.org/10.1016/j.pharmthera.2018.07.007

    CAS  Article  PubMed  Google Scholar 

  37. McMurray F, Patten DA, Harper ME (2016) Reactive Oxygen Species and Oxidative Stress in Obesity-Recent Findings and Empirical Approaches. Obesity (Silver Spring) 24:2301–2310. https://doi.org/10.1002/oby.21654

    CAS  Article  Google Scholar 

  38. Kutzer T, Dick M, Scudamore T, Wiener M, Schwartz T (2020) Antidepressant efficacy and side effect burden: an updated guide for clinicians. Drugs Context. https://doi.org/10.7573/dic.2020-2-2

    Article  PubMed  PubMed Central  Google Scholar 

  39. Tipton KF (2018) 90 years of monoamine oxidase: some progress and some confusion. J Neural Transm (Vienna) 125:1519–1551. https://doi.org/10.1007/s00702-018-1881-5

    CAS  Article  Google Scholar 

  40. Sturza A, Mirica SN, Duicu O, Gheorgheosu D, Noveanu L, Fira-Mladinescu O, Muntean DM (2013) Monoamine oxidase–a inhibition reverses endothelial dysfunction in hypertensive rat aortic rings. Rev Med Chir Soc Med Nat Iasi 117:165–171

    CAS  PubMed  Google Scholar 

  41. Deshwal S, Di Sante M, Di Lisa F, Kaludercic N (2017) Emerging role of monoamine oxidase as a therapeutic target for cardiovascular disease. Curr Opin Pharmacol 33:64–69. https://doi.org/10.1016/j.coph.2017.04.003

    CAS  Article  PubMed  Google Scholar 

  42. Kaludercic N, Carpi A, Menabò R, Di Lisa F, Paolocci N (2011) Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta 1813:1323–1332. https://doi.org/10.1016/j.bbamcr.2010.09.010

    CAS  Article  PubMed  Google Scholar 

  43. Kaludercic N, Mialet-Perez J, Paolocci N, Parini A, Di Lisa F (2014) Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 73:34–42. https://doi.org/10.1016/j.yjmcc.2013.12.032

    CAS  Article  PubMed  Google Scholar 

  44. Muntean DM, Sturza A, Danila MD, Borza C, Duicu OM, Mornos C (2016) The Role of Mitochondrial Reactive Oxygen Species in Cardiovascular Injury and Protective Strategies. Oxid Med Cell Longev 2016:8254942. https://doi.org/10.1155/2016/8254942

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Sturza A, Popoiu CM, Ionica M, Duicu OM, Olariu S, Muntean DM, Boia ES (2019) Monoamine Oxidase-Related Vascular Oxidative Stress in Diseases Associated with Inflammatory Burden. Oxid Med Cell Longev 2019:8954201. https://doi.org/10.1155/2019/8954201

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Utu D, Pantea S, Duicu OM, Muntean DM, Sturza A (2017) Contribution of monoamine oxidases to vascular oxidative stress in patients with end-stage renal disease requiring hemodialysis. Can J Physiol Pharmacol 95:1383–1388. https://doi.org/10.1139/cjpp-2017-0067

    CAS  Article  PubMed  Google Scholar 

  47. Sturza A, Olariu S, Ionică M, Duicu OM, Văduva AO, Boia E, Muntean DM, Popoiu CM (2019) Monoamine oxidase is a source of oxidative stress in obese patients with chronic inflammation (1). Can J Physiol Pharmacol 97:844–849. https://doi.org/10.1139/cjpp-2019-0028

    CAS  Article  PubMed  Google Scholar 

  48. Ratiu C, Utu D, Petrus A, Norbert P, Olariu S, Duicu O, Sturza A, Muntean DM (2018) Monoamine oxidase inhibition improves vascular function and reduces oxidative stress in rats with lipopolysaccharide-induced inflammation. Gen Physiol Biophys 37:687–694. https://doi.org/10.4149/gpb_2018014

    CAS  Article  PubMed  Google Scholar 

  49. Bułdak Ł, Łabuzek K, Bułdak RJ, Machnik G, Bołdys A, Basiak M, Bogusław O (2017) Metformin reduces the expression of NADPH oxidase and increases the expression of antioxidative enzymes in human monocytes/macrophages cultured in vitro. Exp Ther Med 13:794. https://doi.org/10.3892/etm.2016.3973

    Article  PubMed  Google Scholar 

  50. Piwkowska A, Rogacka D, Jankowski M, Angielski S (2013) Metformin reduces NAD(P)H oxidase activity in mouse cultured podocytes through purinergic dependent mechanism by increasing extracellular ATP concentration. Acta Biochim Pol 60:607–612

    PubMed  Google Scholar 

  51. Yu JW, Deng YP, Han X, Ren GF, Cai J, Jiang GJ (2016) Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice. Cardiovasc Diabetol 15:88. https://doi.org/10.1186/s12933-016-0408-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Davis BJ, Xie Z, Viollet B, Zou MH (2006) Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 55:496–505. https://doi.org/10.2337/diabetes.55.02.06.db05-1064

    CAS  Article  PubMed  Google Scholar 

  53. Eriksson L, Nyström T (2014) Activation of AMP-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis. Cardiovasc Diabetol 13:152. https://doi.org/10.1186/s12933-014-0152-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Batchuluun B, Inoguchi T, Sonoda N, Sasaki S, Inoue T, Fujimura Y, Miura D, Takayanagi R (2014) Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis 232:156–164. https://doi.org/10.1016/j.atherosclerosis.2013.10.025

    CAS  Article  PubMed  Google Scholar 

  55. Cheang WS, Tian XY, Wong WT, Lau CW, Lee SS, Chen ZY, Yao X, Wang N, Huang Y (2014) Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5’ adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor δ pathway. Arterioscler Thromb Vasc Biol 34:830–836. https://doi.org/10.1161/atvbaha.113.301938

    CAS  Article  PubMed  Google Scholar 

  56. Pyla R, Osman I, Pichavaram P, Hansen P, Segar L (2014) Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta. Biochem Pharmacol 92:266–279. https://doi.org/10.1016/j.bcp.2014.08.024

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Yee SW, Lin L, Merski M, Keiser MJ, Gupta A, Zhang Y, Chien HC, Shoichet BK, Giacomini KM (2015) Prediction and validation of enzyme and transporter off-targets for metformin. J Pharmacokinet Pharmacodyn 42:463–475. https://doi.org/10.1007/s10928-015-9436-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Sturza A, Duicu OM, Vaduva A, Danila MD, Noveanu L, Varro A, Muntean DM (2015) Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes. Can J Physiol Pharmacol 93:555–561. https://doi.org/10.1139/cjpp-2014-0544

    CAS  Article  PubMed  Google Scholar 

  59. Abudawood M (2019) Diabetes and cancer: A comprehensive review. J Res Med Sci 24:94. https://doi.org/10.4103/jrms.JRMS_242_19

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Shrestha M, Ng A, Al-Ghareeb A, Alenazi F, Gray R (2020) Association between subthreshold depression and self-care behaviors in people with type 2 diabetes: a systematic review of observational studies. Syst Rev 9:45. https://doi.org/10.1186/s13643-020-01302-z

    Article  PubMed  PubMed Central  Google Scholar 

  61. Guo M, Mi J, Jiang QM, Xu JM, Tang YY, Tian G, Wang B (2014) Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharmacol Physiol 41:650–656. https://doi.org/10.1111/1440-1681.12265

    CAS  Article  PubMed  Google Scholar 

  62. Binda C, Aldeco M, Geldenhuys WJ, Tortorici M, Mattevi A, Edmondson DE (2011) Molecular Insights into Human Monoamine Oxidase B Inhibition by the Glitazone Anti-Diabetes Drugs. ACS Med Chem Lett 3:39–42. https://doi.org/10.1021/ml200196p

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The study was funded by the “Victor Babeș” University of Medicine and Pharmacy Timișoara, RO internal grant nr. 6POSTDOC/2020.

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Ionică, L.N., Gaiță, L., Bînă, A.M. et al. Metformin alleviates monoamine oxidase-related vascular oxidative stress and endothelial dysfunction in rats with diet-induced obesity. Mol Cell Biochem 476, 4019–4029 (2021). https://doi.org/10.1007/s11010-021-04194-2

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Keywords

  • Metformin; monoamine oxidase
  • Obesity
  • Diabetes
  • Rats
  • Oxidative stress
  • Endothelial dysfunction