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Vitamin D improves vascular function and decreases monoamine oxidase A expression in experimental diabetes

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Abstract

The active form of vitamin D, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), was reported to improve vascular function in patients with diabetes, yet the underlying mechanisms remain to be fully elucidated. Monoamine oxidase (MAO), a mitochondrial enzyme, with two isoforms (A and B) that generates hydrogen peroxide (H2O2) as by-product, has been recently reported to contribute to the pathogenesis of endothelial dysfunction in diabetes. The present study assessed the interaction between vitamin D and MAO in the vascular wall in the setting of type 1 experimental diabetes. To this aim, diabetes was induced in male Wistar rats via a single injection of streptozotocin (STZ, 50 mg/kg, IP) and 1 month later thoracic aortas were harvested and used for organ bath studies and H2O2 measurements. MAO expression was assessed by immunohistochemistry and RT-PCR. Endothelial function was evaluated in isolated aortic rings in the absence vs. presence of 1,25(OH)2D3 (100 nM, 24 h incubation). In diabetic animals, we found a significant reduction in the endothelial-dependent relaxation to acetylcholine and an increased expression of the MAO-A isoform, respectively. Vitamin D significantly improved vascular function, mitigated oxidative stress and decreased MAO-A expression in diabetic vascular preparations. In conclusion, MAO-A is induced in diabetic aortas and vitamin D can improve diabetes-induced endothelial dysfunction by modulating the MAO-A expression.

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References

  1. Seals DR, Kaplon RE, Gioscia-Ryan RA, LaRocca TJ (2014) You’re only as old as your arteries: translational strategies for preserving vascular endothelial function with aging. Physiology (Bethesda) 29:250–264. https://doi.org/10.1152/physiol.00059.2013

    Article  CAS  Google Scholar 

  2. Burgmaier M, Hellmich M, Marx N, Reith S (2014) A score to quantify coronary plaque vulnerability in high-risk patients with type 2 diabetes: an optical coherence tomography study. Cardiovasc Diabetol 13:117. https://doi.org/10.1186/s12933-014-0117-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bertoluci MC, Ce GV, da Silva AM, Wainstein MV, Boff W, Punales M (2015) Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes. World J Diabetes 6:679–692. https://doi.org/10.4239/wjd.v6.i5.679

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gleissner CA (2015) The vulnerable vessel. Vascular disease in diabetes mellitus. Hamostaseologie 35: 267–271. https://doi.org/10.5482/hamo-14-11-0059

    Article  Google Scholar 

  5. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070. https://doi.org/10.1161/circresaha.110.223545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Teshima Y, Takahashi N, Nishio S, Saito S, Kondo H, Fukui A, Aoki K, Yufu K, Nakagawa M, Saikawa T (2014) Production of reactive oxygen species in the diabetic heart. Roles of mitochondria and NADPH oxidase. Circ J 78:300–306

    Article  CAS  PubMed  Google Scholar 

  7. Brandes RP, Schroder K (2008) Differential vascular functions of Nox family NADPH oxidases. Curr Opin Lipidol 19:513–518. https://doi.org/10.1097/MOL.0b013e32830c91e3

    Article  CAS  PubMed  Google Scholar 

  8. Kaludercic N, Carpi A, Nagayama T, Sivakumaran V, Zhu G, Lai EW, Bedja D, De Mario A, Chen K, Gabrielson KL, Lindsey ML, Pacak K, Takimoto E, Shih JC, Kass DA, Di Lisa F, Paolocci N (2014) Monoamine oxidase B prompts mitochondrial and cardiac dysfunction in pressure overloaded hearts. Antioxid Redox Signal 20:267–280. https://doi.org/10.1089/ars.2012.4616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. Bianchi P, Kunduzova O, Masini E, Cambon C, Bani D, Raimondi L, Seguelas MH, Nistri S, Colucci W, Leducq N, Parini A (2005) Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury. Circulation 112:3297–3305. https://doi.org/10.1161/circulationaha.104.528133

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Anderson EJ, Efird JT, Davies SW, O’Neal WT, Darden TM, Thayne KA, Katunga LA, Kindell LC, Ferguson TB, Anderson CA, Chitwood WR, Koutlas TC, Williams JM, Rodriguez E, Kypson AP (2014) Monoamine oxidase is a major determinant of redox balance in human atrial myocardium and is associated with postoperative atrial fibrillation. J Am Heart Assoc 3:e000713. https://doi.org/10.1161/jaha.113.000713

    Article  PubMed  PubMed Central  Google Scholar 

  13. Manni ME, Rigacci S (2016) Monoamine oxidase is overactivated in left and right ventricles from ischemic hearts: an intriguing therapeutic target. Oxid Med Cell Longev 2016: 4375418. https://doi.org/10.1155/2016/4375418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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

    Article  CAS  PubMed  Google Scholar 

  15. 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. https://doi.org/10.1139/cjpp-2014-0544

    Article  CAS  PubMed  Google Scholar 

  16. 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: 1–7. https://doi.org/10.1139/cjpp-2014-0544

    Article  CAS  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. Muscogiuri G, Nuzzo V, Gatti A, Zuccoli A, Savastano S, Di Somma C, Pivonello R, Orio F, Colao A (2015) Hypovitaminosis D: a novel risk factor for coronary heart disease in type 2 diabetes? Endocrine 51: 268–273. https://doi.org/10.1007/s12020-015-0609-7

    Article  CAS  Google Scholar 

  19. Winckler K, Tarnow L, Lundby-Christensen L, Almdal TP, Wiinberg N, Eiken P, Boesgaard TW (2015) Vitamin D, carotid intima-media thickness and bone structure in patients with type 2 diabetes. Endocr Connect 4:128–135. https://doi.org/10.1530/ec-15-0034

    Article  PubMed  PubMed Central  Google Scholar 

  20. Caraba A, Crisan V, Romosan I, Mozos I, Murariu M (2017) Vitamin D status, disease activity, and endothelial dysfunction in early rheumatoid arthritis patients. Dis Markers 2017:5241012. https://doi.org/10.1155/2017/5241012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Song Y, Wang L, Pittas AG, Del Gobbo LC, Zhang C, Manson JE, Hu FB (2013) Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care 36:1422–1428. https://doi.org/10.2337/dc12-0962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G (2006) Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care 29:722–724

    Article  CAS  PubMed  Google Scholar 

  23. Schiller A, Gadalean F, Schiller O, Timar R, Bob F, Munteanu M, Stoian D, Mihaescu A, Timar B (2015) Vitamin D deficiency–prognostic marker or mortality risk factor in end stage renal disease patients with diabetes mellitus treated with hemodialysis–a prospective multicenter study. PLoS ONE 10:e0126586. https://doi.org/10.1371/journal.pone.0126586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Garcia LA, Ferrini MG, Norris KC, Artaza JN (2013) 1,25(OH)(2)vitamin D(3) enhances myogenic differentiation by modulating the expression of key angiogenic growth factors and angiogenic inhibitors in C(2)C(12) skeletal muscle cells. J Steroid Biochem Mol Biol 133:1–11. https://doi.org/10.1016/j.jsbmb.2012.09.004

    Article  CAS  PubMed  Google Scholar 

  25. Holick MF (2011) Vitamin D: evolutionary, physiological and health perspectives. Curr Drug Targets 12:4–18

    Article  CAS  PubMed  Google Scholar 

  26. Mandarino NR, Junior F, Salgado JV, Lages JS, Filho NS (2015) Is vitamin d deficiency a new risk factor for cardiovascular disease? Open Cardiovasc Med J 9:40–49. https://doi.org/10.2174/1874192401509010040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Menezes AR, Lamb MC, Lavie CJ, DiNicolantonio JJ (2014) Vitamin D and atherosclerosis. Curr Opin Cardiol 29:571–577. https://doi.org/10.1097/hco.0000000000000108

    Article  PubMed  Google Scholar 

  28. Singh J, Merrill ED, Sandesara PB, Schoeneberg L, Dai H, Raghuveer G (2015) Vitamin D, low-grade inflammation and cardiovascular risk in young children: a pilot study. Pediatr Cardiol 36: 1338–1343. https://doi.org/10.1007/s00246-015-1162-0

    Article  Google Scholar 

  29. Somjen D, Kulesza U, Sharon O, Knoll E, Stern N (2014) New vitamin D less-calcemic analog affect human bone cell line and cultured vascular smooth muscle cells similar to other less-calcemic analogs. J Steroid Biochem Mol Biol 140:1–6. https://doi.org/10.1016/j.jsbmb.2013.11.007

    Article  CAS  PubMed  Google Scholar 

  30. Challa AS, Makariou SE, Siomou EC (2015) The relation of vitamin D status with metabolic syndrome in childhood and adolescence: an update. J Pediatr Endocrinol Metab 28: 1235–1245. https://doi.org/10.1515/jpem-2014-0485

    Article  CAS  Google Scholar 

  31. Kavadar G, Demircioglu DT, Ozgonenel L, Emre TY (2015) The relationship between vitamin D status, physical activity and insulin resistance in overweight and obese subjects. Bosn J Basic Med Sci 15:62–66. https://doi.org/10.17305/bjbms.2015.399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rusconi RE, De Cosmi V, Gianluca G, Giavoli C, Agostoni C (2015) Vitamin D insufficiency in obese children and relation with lipid profile. Int J Food Sci Nutr 66:132–134. https://doi.org/10.3109/09637486.2014.959902

    Article  CAS  PubMed  Google Scholar 

  33. Kono K, Fujii H, Nakai K, Goto S, Kitazawa R, Kitazawa S, Shinohara M, Hirata M, Fukagawa M, Nishi S (2013) Anti-oxidative effect of vitamin D analog on incipient vascular lesion in non-obese type 2 diabetic rats. Am J Nephrol 37:167–174. https://doi.org/10.1159/000346808

    Article  CAS  PubMed  Google Scholar 

  34. de Chaumont F, Dallongeville S, Chenouard N, Herve N, Pop S, Provoost T, Meas-Yedid V, Pankajakshan P, Lecomte T, Le Montagner Y, Lagache T, Dufour A, Olivo-Marin JC (2012) Icy: an open bioimage informatics platform for extended reproducible research. Nat Methods 9:690–696. https://doi.org/10.1038/nmeth.2075

    Article  CAS  PubMed  Google Scholar 

  35. 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 431: 37–44. https://doi.org/10.1007/s11010-017-2973-5

    Article  CAS  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. Saif-Elnasr M, Ibrahim IM, Alkady MM (2017) Role of Vitamin D on glycemic control and oxidative stress in type 2 diabetes mellitus. J Res Med Sci 22:22. https://doi.org/10.4103/1735-1995.200278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wimalawansa SJ (2016) Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome. J Steroid Biochem Mol Biol 3: 55–57. https://doi.org/10.1016/j.jsbmb.2016.09.017

    Article  CAS  Google Scholar 

  39. Lips P, Eekhoff M, van Schoor N, Oosterwerff M, de Jongh R, Krul-Poel Y, Simsek S (2016) Vitamin D and type 2 diabetes. J Steroid Biochem Mol Biol 7: 185. https://doi.org/10.1016/j.jsbmb.2016.11.021

    Article  CAS  Google Scholar 

  40. Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD (2008) Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med 25:320–325. https://doi.org/10.1111/j.1464-5491.2007.02360.x

    Article  CAS  PubMed  Google Scholar 

  41. Lin LM, Peng F, Liu YP, Chai DJ, Ning RB, Xu CS, Lin JX (2016) Coadministration of VDR and RXR agonists synergistically alleviates atherosclerosis through inhibition of oxidative stress: An in vivo and in vitro study. Atherosclerosis 251:273–281. https://doi.org/10.1016/j.atherosclerosis.2016.06.005

    Article  CAS  PubMed  Google Scholar 

  42. Manna P, Achari AE, Jain SK (2018) 1,25(OH)2-vitamin D3 upregulates glucose uptake mediated by SIRT1/IRS1/GLUT4 signaling cascade in C2C12 myotubes. Mol Cell Biochem 444:103–108. https://doi.org/10.1007/s11010-017-3235-2

    Article  CAS  PubMed  Google Scholar 

  43. Takeda M, Yamashita T, Sasaki N, Nakajima K, Kita T, Shinohara M, Ishida T, Hirata K (2010) Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions. Arterioscler Thromb Vasc Biol 30:2495–2503. https://doi.org/10.1161/atvbaha.110.215459

    Article  CAS  PubMed  Google Scholar 

  44. Wong MS, Leisegang MS, Kruse C, Vogel J, Schurmann C, Dehne N, Weigert A, Herrmann E, Brune B, Shah AM, Steinhilber D, Offermanns S, Carmeliet G, Badenhoop K, Schroder K, Brandes RP (2014) Vitamin D promotes vascular regeneration. Circulation 130:976–986. https://doi.org/10.1161/circulationaha.114.010650

    Article  CAS  PubMed  Google Scholar 

  45. Sturza A, Duicu O, Vaduva A, Noveanu L, Danila M, Privistirescu A, Timar R, Muntean D, Munteanu M (2015) Reduction of rage expression by vitamin D in isolated diabetic rat aortas. Revista De Chimie 66:1509–1512

    CAS  Google Scholar 

  46. Sena CM, Pereira AM, Seica R (2013) Endothelial dysfunction - a major mediator of diabetic vascular disease. Biochim Biophys Acta 1832:2216–2231. https://doi.org/10.1016/j.bbadis.2013.08.006

    Article  CAS  PubMed  Google Scholar 

  47. Vaquer G, Magous R, Cros G, Wojtusciszyn A, Renard E, Chevassus H, Petit P, Lajoix AD, Oiry C (2013) Short-term intravenous insulin infusion is associated with reduced expression of NADPH oxidase p47(phox) subunit in monocytes from type 2 diabetes patients. Fundam Clin Pharmacol 27:669–671. https://doi.org/10.1111/j.1472-8206.2012.01057.x

    Article  CAS  PubMed  Google Scholar 

  48. Deshwal S, Forkink M, Hu CH, Buonincontri G, Antonucci S, Di Sante M, Murphy MP, Paolocci N, Mochly-Rosen D, Krieg T, Di Lisa F, Kaludercic N (2018) Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes. https://doi.org/10.1038/s41418-018-0071-1

  49. Song MS, Matveychuk D, MacKenzie EM, Duchcherer M, Mousseau DD, Baker GB (2013) An update on amine oxidase inhibitors: multifaceted drugs. Prog Neuropsychopharmacol Biol Psychiatry 44:118–124. https://doi.org/10.1016/j.pnpbp.2013.02.001

    Article  CAS  PubMed  Google Scholar 

  50. Youdim MB, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7:295–309. https://doi.org/10.1038/nrn1883

    Article  CAS  PubMed  Google Scholar 

  51. Knekt P, Kilkkinen A, Rissanen H, Marniemi J, Saaksjarvi K, Heliovaara M (2010) Serum vitamin D and the risk of Parkinson disease. Arch Neurol 67:808–811. https://doi.org/10.1001/archneurol.2010.120

    Article  PubMed  PubMed Central  Google Scholar 

  52. Harms LR, Eyles DW, McGrath JJ, Mackay-Sim A, Burne TH (2008) Developmental vitamin D deficiency alters adult behaviour in 129/SvJ and C57BL/6J mice. Behav Brain Res 187:343–350. https://doi.org/10.1016/j.bbr.2007.09.032

    Article  CAS  PubMed  Google Scholar 

  53. Cass WA, Smith MP, Peters LE (2006) Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine. Ann N Y Acad Sci 1074:261–271. https://doi.org/10.1196/annals.1369.023

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The study was funded by the institutional grant of “Victor Babeş” University of Medicine and Pharmacy Timișoara code PIII-C5-PCFI-2017/2018-01.

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Sturza, A., Văduva, A., Uțu, D. et al. Vitamin D improves vascular function and decreases monoamine oxidase A expression in experimental diabetes. Mol Cell Biochem 453, 33–40 (2019). https://doi.org/10.1007/s11010-018-3429-2

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