Effects ofgenipin on no synthesis and ishemia/reperfusion-induced oxidaive stress in old rathearts
Y.V. Goshovska, Y.P. Korkach, T.V. Shimanskaya, A.V. Kotsuruba, V.F. Sagach
Ін-т фізіології ім. О.О. Богомольця НАН України, Київ
Abstract
Genipin is aglycone of geniposide, one of the active compounds of Gardenia gasminoides Ellis. The gardenia fruit extract has been used in traditional Chinese medicine to relieve the symptoms of type 2 diabetes that is accompanied with extensive oxidative stress and endothelial dysfunction of NO production. Besides, genipin was shown to inhibit UCP-depended proton leak through the inner mitochondrial membrane that leads to increased membrane potential and ATP production. We studied the effects of genipin at ischemia/reperfusion-in-duced oxidative stress and activity of NOS isozymes using Langendorf perfused old rat heart model. Ischemia/reperfusion is well-known oxidative agent, and showed significant increasing of superoxide radical, hydrogen peroxide and hydroxyl radical. Genipin application in doze 10-5 mol/L for 15 min before prolonged ischemia exerted powerful antiradical and antilipoperoxidative effects. Heart ischemia/reperfusion was supported with peroxynitrite generation and nitrozative stress. We demonstrated the inhibitory property of genipin on iNOS expression that possibly occurs via protein kinase A inhibition and stabilization of I-kB-NF-kB complex. Genipin stimulated cNOS activity seemingly activating PI3K/Akt signaling pathway. Although, post-ischemic recovery of cardiodynamic parameters of old rat hearts were depressed due to “switching off the NO production by inducible NOS which is important in early period of reperfusion. Thus, we conclude that genipin is powerfull antioxidant and posses insulin-like activity due to its property of managing the NO production at intracellular signal transduction cascade level.
References
- Барабой В.А., Суткова Д.А. Окислительно-анти-оксидантный гомеостаз в норме и при патологи -К.: Наук. думка, 1997. - ч. 2. - С. 128-130.
- Гошовська Ю.В., Лісовий О.О., Шиманська Т.В., Сагач В.Ф. Зміни експресії генів UCP2 та UCP3, функціонального стану і кисневої вартості роботи міокарда в умовах старіння та ішемії–реперфузії // Фізіол. журн. - 55, №3. -С. 26-36.
- Коркач Ю.П., Рудик О.В., Коцюруба А.В. та ін. Участь синтезу оксиду азоту та супероксид-аніона в механізмі протекторної дії екдистерону в мітохонд-ріях серця щурів при стрептозотоциніндукованому діабеті // Фізіол. журн. - 2007. - 53, №5. - С.22-28.
- Шугалей B.C., Козина А.С. Содержание мочевины и активность аргиназы в органах крыс при аклима-тизации к холоду // Физиол. журн. СССР. - 1977. -№8. -С. 1199-1202.
- Becker L.B., Vanden Hoek T.L., Shao Z-H. et al. Generation of supeoxide in cardiomyocytes during ischemia before reperfussion // Amer. J. Physiol. - 1999. - 277. -P. 2240-2246.
- Bolli R. Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research // J. Mol. Cell Cardiol. - 2001. - 33. -P. 1897-1918.
- Boyde T.R, Rahmatullah M. Optimization of conditions for the colorimetric determination of citrulline, using diacetyl monoxime // Anal. Biochem. - 1980. -107, №2. -P. 424-431.
- Brand M.D., Affourtit C, Esteves T.C. et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins // Free Rad. Biol. Med. - 2004. - 37. - P. 755-767.
- 9. Branford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye-binding // Anal. Biochem. - 1976. - 72. - P. 248-254.
- 10. Cai H., Li Z., Dikalov S., Holland S.M. et al. NAD(P)H oxidase-derived hydrogen peroxide mediates endothelial nitric oxide production in response to angiotensin II // J. Biol. Chem. - 2002. - 277, №50. -P. 48311–48317.
- Das D.K., Maulik N. Conversion of death signal into survival signal by redox signaling // Biochem. (Mosc). -2000. - 69, № 1. -P. 10-17.
- Dimmeler S., Fleming I., Fisslthaler B. et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation // Nature. - 1999. -399. – P. 601-605.
- Echtay K.S., Murphy M.P., Smith R.A. et al. Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants // J. Biol. Chem. - 2002. - 277, № 49. - P. 47129-47135.
- Green L.C., Wagner D.A., Glogowski J. et al. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids // Anal. Biochem. - 1982. -126, № 1. - P. 131-138.
- Gutierrez J., Ballinger S.W., Darley-Usmar V.M., Landar A. Free radicals, mitochondria, and oxidized lipids. The emerging role in signal transduction in vascular cells // Circulat. Res. - 2006. - 99. - P. 924-932.
- Heger J., Godecke A., Flogel U. et al. Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction // Ibid. - 2002. -90. - P. 93-99.
- Humphries K.M., Yoo Y., Szweda L.I. Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal // Biochem. - 1998. - 37, № 2. - P. 552-557.
- Huwiler M., Kohler H. Pseudo-catalytic degradation of hydrogen peroxide in the lactoperoxidase/H2O2/io-dide system //Eur. J. Biochem. - 1984. - 141, № 1. -P. 69-74.
- 19. Jones S.P., Bolli R. The ubiquitous role of nitric oxide in cardioprotection // J. Mol. Cell Cardiol. - 2006. -40. - P. 16-23.
- 20. Koo H.J., Song Y.S., Kim H.J. et al. Antiinflammatory effects of genipin, an active principle of gardenia // Eur. J. Pharmacol. - 2004. - 495. - P. 201-208.
- Kuthan H., Ullrich V., Estabrook R.W. A quantitative test for superoxide radicals produced in biological systems // Biochem. J. - 1982. - 203, № 3. - P. 551-558.
- Lesnefsky E.J., Hoppel C.L. Ischemia-reperfusion injury in the aged heart: role of mitochondria // Arch. Biochem. Biophys. - 2003. - 420, № 2. - P. 287-297.
- McCabe T.J., Fulton D., Roman L.J., Sessa W.C. Enhanced electron flux and reduced calmodulin dissociation may explain “calcium-independent” eNOS activation by phosphorylation // J. Biol. Chem. - 2000. -275. - P. 6123-6128.
- Nair V., Cooper C.S., Vietti D.E., Turner G.A. The chemistry of lipid peroxidation metabolites: crosslin-king reactions of malondialde-hyde // Lipids. -1986. -21. - P. 6–10.
- Nistri S., Bani D. Relaxin receptors and nitric oxide synthases: search for the missing link // Reprod. Biol. Endocrinol. - 2003. - 1. - P.5.
- Prendergast B.D., Sagach V.F., Shah A.M. Basal release of nitric oxide augments the Frank-Starling response in the isolated heart // Circulation. - 1997. - 96, № 4. -P.1320-1329
- Tsukahara H., Miura M., Tsuchida S. et al. Effect of nitric oxide synthase inhibitors on bone metabolism in growing rats // Amer. J. Physiol. - 1996. - 270, № 5, Pt 1. -P. E840–E845.
- Van den Hoek T.L., Becker L.B., Shao Z. et al. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes // J. Biol. Chem. - 1998. - 273. - P. 18092-18098.
- 29. Vidal-Puig A.J., Grujic D., Zhang C.Y et al. Energy metabolism in uncoupling protein 3 gene knockout mice // J. Biol. Chem. - 2000. - 275, № 21. - P. 16258-16266.
- 30. West M.B., Rokosh G., Obal D. et al. Cardiac myocyte-specific expression of inducible nitric oxide synthaseprotects against ischemia/reperfusion injury by preventing mitochondrial permeability transition // Circulation. – 2008. – 118. – P. 1970–1978. 31. Zhang C.Y., Parton L.E., Ye C.P. et al. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets // Cell Metab. - 2006. - 3, №6. - P. 417-427. 32. Zhen J., Lu H., Wang X.Q. et al. Upregulation of endothelial and inducible nitric oxide synthase expression by reactive oxygen species // Amer. J. Hypertens. -2008. - 21, № 1. -P. 28-34.
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