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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2022; 68(1): 3-12

The regulation of mitochondrial NO synthase activity under nitroglycerine application in rat heart and liver mitochondria

O.V. Akopova, Yu. P. Korkach, V. F. Sagach

    O.O. Bogomoletz Institute of Physiology of National Academy of Science of Ukraine, Kyiv, Ukraine
DOI: https://doi.org/10.15407/fz68.01.003


Abstract

Nitroglycerine (NG) affords cardioprotection via NO formation, but the impact of NG application on reactive nitrogen species (RNS) metabolism remains little studied yet. Mitochondrial NO synthase (mtNOS) is an important endogenous source of RNS. Our aim was to study the effect of NG application on mtNOS activity and RNS production in rat heart and liver mitochondria. Different regulation of mtNOS activity in the heart and liver under NG treatment was found. While in heart mitochondria it increased dose-dependently, in liver mitochondria only moderate elevation and bell-shaped dose dependence of mtNOS activity on NG was observed. Nitrite and nitrate, which are the end products of L-arginine transformation by NOS, showed similar dose dependence on NG. To find an explanation for the observed dependences, we studied the effects of NG administration on the activity of arginase which competes with NOS for physiological substrate, Larginine. A strong reciprocal dependence between mtNOS and arginase activities was found. As we observed, the arginase activity increased under NG application. However, while in heart mitochondria high mtNOS activity agreed with moderate arginase activation, in liver mitochondria high arginase activity coincided with suppression of mtNOS activity at high doses of NG. Low arginase and high mtNOS activities observed in heart mitochondria were consistent with high NO2 − and NO3 − production and low hydroperoxide (H2O2) formation, whereas high arginase activity in liver mitochondria was accompanied by the reduction of NO2− /NO3− formation and simultaneous elevation of H2O2 production. A linear correlation between the arginase activity and hydroperoxide formation was found. We came to the conclusion that under NG administration arginase activation resulted in reciprocal regulation of RNS and ROS production in mitochondria, dependent on the proportion of mtNOS to arginase activity. Suppression of RNS metabolism could be the cause of ROS overproduction caused by high arginase and low mtNOS activity.

Keywords: heart; liver; mitochondria; NOS; arginase; reactive nitrogen and oxygen species.

Full text: (PDF, in English)

References

  1. Ignarro LJ, Napoli C, Loscalzo J. Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide. Circ. Res. 2002;90(1):21-8. CrossRef PubMed
  2. Andreadou I, Schulz R, Papapetropoulos R, Turan B, Ytrehus K, Ferdinandy P, Daiber A, Di Lisa F. The role of mitochondrial reactive oxygen species, NO and H2S in ischemia. reperfusion injury and cardioprotection. J Cell Mol Med. 2020;24:6510-22. CrossRef PubMed PubMedCentral
  3. Varga ZV, Giricz Z, Liaudet L, et al. Interplay of oxidative, nitrosative. nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy. Biochim Biophys Acta. 2015;1852:232-42. CrossRef PubMed PubMedCentral
  4. Radi R, Beckman JC, Bush KM, Freeman BA. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys. 1991;288: 481-7. CrossRef
  5. Reutov VP, Sorokina EG, Ohotin VE, Kositsyn NS. Cyclic transformations of nitric oxide in the organism of mammals. M: Nauka. 1998. [in Russian].
  6. Akopova O, Kotsiuruba A, Korkach Y, Kolchinskaya L, Nosar V, Gavenauskas B, Serebrovska Z, Mankovska I, Sagach V. The effect of NO donor on calcium uptake and reactive nitrogen species production in mitochondria. Cell Physiol Biochem. 2016; 39(1):193-204. CrossRef PubMed
  7. Bibli S-I, Papapetropoulos A, Iliodromitis EK, et al. Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug. Cardiovascul Res. 2019;115:625-36. CrossRef PubMed PubMedCentral
  8. Brookes PS. Mitochondrial nitric oxide synthase. Mitochondrion. 2004;3:187-204. CrossRef PubMed
  9. Borutaite V, Brown GC. S-nitrosothiol inhibition of mitochondrial complex I causes a reversible increase in mitochondrial hydrogen peroxide production. Biochim Biophys Acta. 2006;1757:562-6. CrossRef PubMed
  10. Ullrich V, Schildknecht S. Sensing hypoxia by mitochondria: a unifying hypothesis involving s-nitrosation. Antioxid Redox Signal. 2014;20:325-38. CrossRef PubMed
  11. Nedospasov AA. Competition involving biogenic NO. Biochemistry. 1998;63(7):744-65.
  12. Durante W, Johnson FK, Johnson RA. Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol. 2007;34(9): 906-11. CrossRef PubMed PubMedCentral
  13. Wu G, Morris SM. Arginine metabolism: nitric oxide and beyond. Biochem. J. 1998;336:1-17. CrossRef PubMed PubMedCentral
  14. Elms S, Chen F, Wang Y, Qian J, Askari B, Yu Y, Pandey D, Iddings J, Caldwell RB, Fulton DJ. Insights into the arginine paradox: evidence against the importance of subcellular location of arginase and eNOS. Am J Physiol Heart Circ Physiol. 2013;305(5): H651-H66. CrossRef PubMed PubMedCentral
  15. Sagach VF, Baziluk OV, Stepanenko LG, Korkach YuP, Kotsuruba AV. ACE inhibitor enalapril action on nitric oxide synthesis, oxidative metabolism, and vascular tone of aging rat. Fiziol Zh. 2007;53(4):15-26. [Ukrainian].
  16. Korkach YuP, Kotsuruba AV, Prysiazhna OD, Mogylnytska LD, Sagach VF. NO-dependent mechanisms of ecdysterone protective action on heart and vessels at streptozotocin-induced diabetes mellitus in rats. Fiziol Zh. 2007;53(3):3-8. [Ukrainian].
  17. Kotsuruba A, Korkach Yu, Talanov S, Basiluk O, Stepanenko L, Sahach V. Arginase-nitric oxide synthase system changes due to adaptation to swimming in adult and aged rat hearts. Fiziol Zh. 2012;58(1):27-35. [Ukrainian].
  18. Buga GM, Singh R, Pervin S, Rogers NE, Schmitz DA, Jenkinson CP, Cederbaum SD, Ignarro LJ. Arginase activity in endothelial cells: inhibition by NG-hydroxy-Larginine during high-output NO production. Am J Physiol 1996;271:H1988-H98. CrossRef PubMed
  19. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrite, nitrate and [15N]nitrate in biological fluids. Anal Biochem 1982;126:131-8. CrossRef
  20. Korkach YuP, Dudchenko NO, Kotsiuruba AV. The role of non-heme iron in the protection effect of ecdysterone on the development of streptozotocin-induced hypoglycemia in rats. Ukr Biochem J. 2008;80(1):46-51.
  21. Percival MD, Ouellet M, Campagnolo Ch, Claveau D, Li Ch. Inhibition of cathepsin K by nitric oxide donors: evidence for the formation of mixed disulfides and a sulfenic acid. Biochemistry. 1999;38:13574-83. CrossRef PubMed
  22. Huwiler M, Kohler H. Pseudo-catalytic degradation of hydrogen peroxide in the lactoperoxidase. H2O2. iodide system. Eur J Biochem. 1984;141:69-74. CrossRef PubMed
    23. Dedkova EN, Ji X, Lipsius SL, Blatter LA. Mitochondrial calcium uptake stimulates nitric oxide production in mitochondria of bovine vascular endothelial cells. Am J Physiol. 2004;286:C406-C15. R CrossRef PubMed

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