Changes in the asymmetric dimethylarginine and endothelial nitric oxide synthase levels in pathogenesis of experimental diabetic retinopathy
Keywords:
Diabetic retinopathy, endothelial dysfunction, asymmetric dimethylarginine, endothelial NO-synthase, comparative description.
Abstract
Endothelial dysfunction associated with impaired nitric oxide excretion plays an important role in the onset and progression of diabetic retinopathy. It has been proven that a decrease in the activity of endothelial NO-synthase (еNО-S), the inhibitor of which is asymmetric dimethylarginine (ADMA), plays an important role in this. Objective: to study the level of asymmetric dimethylarginine and endothelial nitric oxide synthase at different stages of development of diabetic retinopathy in the experiment. The study was conducted in Wistar white rats of 180-200 g weight. According to the tasks, the animals were separated into 2 groups as follows: group 1 – 60 intact animals, group 2 – 60 animals with simulated diabetic retinopathy without further correction. Type 2 diabetes mellitus and diabetic retinopathy were simulated through intraperitoneal administration of Streptozotocin (Sigma, USA) diluted in 0.1M citrate buffer with pH=4.5. Streptozotocin dose of 55 mg per kg of animal weight was divided into two administrations. The streptozotocin intake was preceded by a 28-day high-fat diet. Our study showed impaired endothelial function in diabetic retinopathy, as evidenced by an increased ADMA level (p<0.001). We have determined a stepwise increase of asymmetric dimethylarginine level in blood of rats with simulated pathology which is apparent in its highest at phase 3. Pathogenetic effect of increased ADMA on еNО-S activity was verified at all experimental stages, Impairment of physiological nitric oxide synthesis in simulated pathology has been proved as evidenced by reduced activity of endothelial NO-synthase yet on the 30th day with further negative dynamics up to the 180th day (p<0.001 compared with the intact group findings).
References
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doi.org/10.1016/S0008-6363(99)00162-5
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[22] Pasechnikova, N. V., & Moroz, O. A. (2015). Protective action of quercetin and lipoate on functional groups of retinal proteins under simulated diabetes. Journal of Ophthalmology, 3, 76-81.
[23] Perticone F., Sciacqua A., Maio R., Perticone, M., Maas, R., Boger, R. H. … Zoccali, C. (2005). Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension. J. Am. Coll. Cardiol., 46, 518-523.
[24] Pollock, J. S., Forstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H., Nakane, M., & Murad, F. (1991). Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc. Natl. Acad. Sci. U.S.A., 88, 10480-10484. doi: 10.1073/pnas.88.23.10480
[25] Rees, D. D., Palmer, R. M., Schulz, R., Hodson, H. F., & Moncada, S. (1990). Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br. J. Pharmacol., 101(3), 746-752. doi: 10.1111/j.1476-5381.1990.tb14151.x
[26] Rizzoni, D., Porteri, E., Castellano, M., Bettoni, G., Muiesan, M. L., Tiberio, G. … Agabiti-Rosei, E. (1998). Endothelial Dysfunction in Hypertension Is Independent From the Etiology and From Vascular Structure. Hypertension, 31, 335-341. doi: 10.1161/01.hyp.31.1.335
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[28] Saitoh, M., Osanai, T., Kamada, T., Matsunaga, T., Ishizaka, H., Hanada, H., & Okumura, K. (2003). High plasma level of asymmetric dimethylarginine in patients with acutely exacerbated congestive heart failure: role in reduction of plasma nitric oxide level. Heart Vessels, 18, 177-182. doi: 10.1007/s00380-003-0715-y
[29] Smirnova, I. V., Kajstura, M., Sawamura, T., & Goligorsky, M. S. (2004). Asymmetric dimethylarginine upregulates TOX-1 in activated macrophages: role in foam cell formation. Am. J. Physiol. Heart Circ. Physiol., 287(2), H782-9. doi: 10.1152/ajpheart.00822.2003.
[30] Stuhlinger, M. C., Oka, R. K., Graf, Е. Ё., Schmölzer, I., Upson, B. M., Kapoor, O. … Cooke, J. P. (2003). Endothelial dysfunction induced by hyperhomocyst (e) inemia: role of asymmetric dimethylarginine. Circulation, 108(8), 933-938. doi: 10.1161/01.CIR.0000085067.55901.89
[31] Stuhlinger, M. C., Tsao, P. S., Her, J. H., Kimoto, M., Balint, R. F. & Cooke, J. P. (2001). Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation, 104(21), 2569-2575. doi: 10.1161/hc4601.098514.
[32] Teerlink, Т. (2005). ADMA metabolism and clearance. Vasc. Med., 10(1), 73-81. doi: 10.1191/1358863x05vm597oa.
[33] Teerlink, T. (2005). Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance. Clin. Chem. Lab. Med., 43, 1130-1138. doi: 10.1515/CCLM.2005.197.
[34] Tin, K. Y., Ito, A., Asagami, T., Tsao, P. S., Adimoolam, S., Kimoto, M. … Cooke, J. P. (2002). Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation, 106, 987-992. doi: 10.1161/01.cir.0000027109.14149.67
[35] Ueno, S., Morino, H., Sano, A., & Kakimoto Y. (1990). Purification and characterization of D-3-aminoisobutyrate-pyruvate aminotransferase from rat liver. Biochim. Biophys. Acta., 1033(2), 169-175. https://doi.org/10.1016/0304-4165(90)90008-K
[36] Vallance, P., Leone, A., Calver, A., Collier, J., & Moncada, S. (1992). Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet, 339(8793), 572-575. doi: 10.1016/0140-6736(92)90865-z
[37] Vallance, P., Leone, A., Calver, A., Collier, J., & Moncada, S. (1992). Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J. Cardiovasc. Pharmacol., 20, 12, 60-62. doi: 10.1097/00005344-199204002-00018.
[38] Zoccali, C., Benedetto, F. A., Maas, R., Mallamaci, F., Tripepi, G., Malatino, L. S., & Böger, R. (2002). Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J. Am. Soc. Nephrol., 13, 490-496.
[39] Zhloba, A. A. (2007). Asymmetric dimethylarginine as a mediator and marker for endothelial dysfunction development. Arterial Hypertension, 13(2), 119-127.
[2] Bode-Boger, S. M., Scalera, F., & Martens-Lobenlioffer, J. (2005). Asymmetric dimethylarginine (ADMA) accelerates cell senescence. Vasc. Med., 10(1), 65-71. https://doi.org/10.1191/1358863x05vm606oa
[3] Boger, R. H. (2004). Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “L-arginine paradox” and acts as a novel cardiovascular risk factor. J. Nutr., 134(10), 2842S-2847S. doi: 10.1093/jn/134.10.2842S
[4] Boger, R. H., Bode-Boger, S. M., Mugge, A., Kienke, S., Brandes, R., Dwenger, A., & Frolich, J. C. (1995). Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production. Atherosclerosis, 117, 273-284. doi: 10.1016/0021-9150(95)05582-h
[5] Boger, R. H., Bode-Boger, S. M., Szuba, A., Tsao, P. S., Chan, J. R., Tangphao, O. … Cooke, J. P. (1998). Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation, 98(18), 1842-1847. doi: 10.1161/01.cir.98.18.1842.
[6] Boger, R. H., Bode-Boger, S. M., Tsao, P. S., Lin, P. S., Chan, J. R., & Cooke, J. P. (2000). An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes. JACC, 36, 2287-2295. doi: 10.1016/s0735-1097(00)01013-5.
[7] Boger, R. H., Cooke, J. P., & Vallance, P. (2005). ADMA: an emerging cardiovascular risk factor. Vasc. Med., 10, 1, S1-S2.
[8] Buryal, V. V. (2014). Role of asymmetric dimethylarginine in formation of pathophysiologic mechanisms for arterial pressure control impairments. Young scientist, 6(9), 142-144.
[9] Chan, J. R., Boger, R. H., Bode-Boger, S. M., Tangphao, O., Tsao, P. S., Blaschke, T. F., & Cooke, J. P. (2000). Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Thromb Vasc Biol., 20, 1040-1046. https://doi.org/10.1161/01.ATV.20.4.1040
[10] Creager, M. A., Gallagher, S. J., Girerd, X. J., Coleman, S. M., Dzau, V. J. & Cooke, J. P. (1992). L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J. Clin. Invest., 90, 1248-1253.
[11] Eid, H.,M., Amesen, H., Hjerkiim, E. M., Lyberg, T., & Seljeflot, I. (2004). Relationship between obesity, smoking, and the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine. Metabolism, 53(12), 1574-1579. doi.org/10.1016/j.metabol.2004.06.026
[12] Faraci, F. M., Brian, J. E. J., & Heistad, D. D. (1995). Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am. J. Physiol., 269, H1522-H1527. doi.org/10.1152/ajpheart.1995.269.5.H1522
[13] Galyavich, A. S., & Gaynutdinov, E. R. (2009). Asymmetric dimethylarginine and nitric oxide metabolism products in patients with acute and chronic forms of coronary heart disease. Cardiovascular therapy and prevention, 8(1), 31-34.
[14] Gavrilova, N. A., & Tishchenko, O. E. (2011). The impact of sulodexide on the endothelial functional state in patients with diabetes mellitus and diabetic retinopathy. Diabetes Mellitus, 2, 66-68.
[15] Kaydash, O. A., Ivanov, V. V., Vengerovskyi, A. I., Buyko Ye. Ye., & Shchepetkin, I. A. (2020) Investigational model of Type 2 diabetes mellitus in rats caused by a diet with high content of fats and low dosage of streptozotocin. The Siberian Medicine Bulletin, 19(2), 41-47.
[16] Kielstein, J. T., Tsikas, D., Fliser, D. (2006). Effects of asymmetric dimethylarginine (ADMA) infusion in humans. Eur. J. Clin. Pharmacol., 62(13), 39-44. doi: 10.1007/s00228-005-0010-1
[17] Leiper, J., & Vallance, P. (1999). Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc. Res., 43(3), 542-548.
doi.org/10.1016/S0008-6363(99)00162-5
[18] Lu, C. W., Xiong, Y., & He, P. (2006). Dimethylarginine dimethylaminohydr olase-2 overexpression improves impaired nitric oxide synthesis of endothelial cells induced by glycated protein. Nitric Oxide: Biology and Chemistry, 16(1):94-103. doi: 10.1016/j.niox.2006.07.006
[19] MacAllister, R. J., Parry, H., Kimoto, M., Ogawa, T., Russell, R. J., Hodson, H., … Vallance, P. (1996). Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br. J. Pharmacol., 119(8), 1533-1540. doi: 10.1111/j.1476-5381.1996.tb16069.x.
[20] Nonaka, S., Tsunoda, M., Imai, K., & Funatsu, T. (2005). High-performance liquid chromatographic assay of N(G)-monomethyl-L-arginine, N(G), N(G)-dimethyl-L-arginine, and N(G), N(G)’-dimethyl-L-arginine using 4-fluoro-7-nitro-2, 1,3-benzoxadiazole as a fluorescent reagent. J. Chromatogr., A 1066, 41-45. doi: 10.1016/j.chroma.2005.01.052
[21] Paiva, H., Lehtimaki, T., Laakso, J., Ruokonen, I., Rantalaiho, V., Wirta, O. … Laaksonen, R. (2003). Plasma concentrations of asymmetric dimethylarginine in type 2 diabetes associate with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy. Metabolism, 52, 303-307. doi: 10.1053/meta.2003.50048
[22] Pasechnikova, N. V., & Moroz, O. A. (2015). Protective action of quercetin and lipoate on functional groups of retinal proteins under simulated diabetes. Journal of Ophthalmology, 3, 76-81.
[23] Perticone F., Sciacqua A., Maio R., Perticone, M., Maas, R., Boger, R. H. … Zoccali, C. (2005). Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension. J. Am. Coll. Cardiol., 46, 518-523.
[24] Pollock, J. S., Forstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H., Nakane, M., & Murad, F. (1991). Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc. Natl. Acad. Sci. U.S.A., 88, 10480-10484. doi: 10.1073/pnas.88.23.10480
[25] Rees, D. D., Palmer, R. M., Schulz, R., Hodson, H. F., & Moncada, S. (1990). Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br. J. Pharmacol., 101(3), 746-752. doi: 10.1111/j.1476-5381.1990.tb14151.x
[26] Rizzoni, D., Porteri, E., Castellano, M., Bettoni, G., Muiesan, M. L., Tiberio, G. … Agabiti-Rosei, E. (1998). Endothelial Dysfunction in Hypertension Is Independent From the Etiology and From Vascular Structure. Hypertension, 31, 335-341. doi: 10.1161/01.hyp.31.1.335
[27] Rodionov, R. N., Blokhin, I. O., Galagudza, M. M., Shlyakhto, E. V., & Lentz, S. R. (2008). Asymmetric dimethylarginine and its role in aetiology and pathogenesis of cardiovascular diseases. Arterial hypertension, 4, 306-314.
[28] Saitoh, M., Osanai, T., Kamada, T., Matsunaga, T., Ishizaka, H., Hanada, H., & Okumura, K. (2003). High plasma level of asymmetric dimethylarginine in patients with acutely exacerbated congestive heart failure: role in reduction of plasma nitric oxide level. Heart Vessels, 18, 177-182. doi: 10.1007/s00380-003-0715-y
[29] Smirnova, I. V., Kajstura, M., Sawamura, T., & Goligorsky, M. S. (2004). Asymmetric dimethylarginine upregulates TOX-1 in activated macrophages: role in foam cell formation. Am. J. Physiol. Heart Circ. Physiol., 287(2), H782-9. doi: 10.1152/ajpheart.00822.2003.
[30] Stuhlinger, M. C., Oka, R. K., Graf, Е. Ё., Schmölzer, I., Upson, B. M., Kapoor, O. … Cooke, J. P. (2003). Endothelial dysfunction induced by hyperhomocyst (e) inemia: role of asymmetric dimethylarginine. Circulation, 108(8), 933-938. doi: 10.1161/01.CIR.0000085067.55901.89
[31] Stuhlinger, M. C., Tsao, P. S., Her, J. H., Kimoto, M., Balint, R. F. & Cooke, J. P. (2001). Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation, 104(21), 2569-2575. doi: 10.1161/hc4601.098514.
[32] Teerlink, Т. (2005). ADMA metabolism and clearance. Vasc. Med., 10(1), 73-81. doi: 10.1191/1358863x05vm597oa.
[33] Teerlink, T. (2005). Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance. Clin. Chem. Lab. Med., 43, 1130-1138. doi: 10.1515/CCLM.2005.197.
[34] Tin, K. Y., Ito, A., Asagami, T., Tsao, P. S., Adimoolam, S., Kimoto, M. … Cooke, J. P. (2002). Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation, 106, 987-992. doi: 10.1161/01.cir.0000027109.14149.67
[35] Ueno, S., Morino, H., Sano, A., & Kakimoto Y. (1990). Purification and characterization of D-3-aminoisobutyrate-pyruvate aminotransferase from rat liver. Biochim. Biophys. Acta., 1033(2), 169-175. https://doi.org/10.1016/0304-4165(90)90008-K
[36] Vallance, P., Leone, A., Calver, A., Collier, J., & Moncada, S. (1992). Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet, 339(8793), 572-575. doi: 10.1016/0140-6736(92)90865-z
[37] Vallance, P., Leone, A., Calver, A., Collier, J., & Moncada, S. (1992). Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J. Cardiovasc. Pharmacol., 20, 12, 60-62. doi: 10.1097/00005344-199204002-00018.
[38] Zoccali, C., Benedetto, F. A., Maas, R., Mallamaci, F., Tripepi, G., Malatino, L. S., & Böger, R. (2002). Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J. Am. Soc. Nephrol., 13, 490-496.
[39] Zhloba, A. A. (2007). Asymmetric dimethylarginine as a mediator and marker for endothelial dysfunction development. Arterial Hypertension, 13(2), 119-127.
Published
2020-10-13
How to Cite
Sirman, Y., Savytskyi, I., & Preys, N. (2020). Changes in the asymmetric dimethylarginine and endothelial nitric oxide synthase levels in pathogenesis of experimental diabetic retinopathy. Reports of Morphology, 26(3), 69-74. https://doi.org/10.31393/morphology-journal-2020-26(3)-10
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