EFFECTS OF GLUTATHIONE ON THE EXPRESSION OF ATP-SENSITIVE POTASSIUM CHANNELS, MITOCHONDRIAL PORES, AND ON OXIDATIVE STRESS IN THE HEART OF OLD RATS
N.A. Strutynska, Yu.V. Goshovska, Yu.P. Korkach, L.A. Mys, R.B. Strutynskyi, V.F. Sagach
O.O. Bogomoletz Institute of Physiology National Academy of Science of Ukraine, Kyiv, Ukraine
DOI: https://doi.org/10.15407/fz66.06.066
Abstract
The effects of a single injection of the reduced form of
glutathione on the expression of the KCNJ8 and KCNJ11
genes encoding Kir6.1 and Kir6.2 subunits of ATP-sensitive
potassium (KATP) channels and on Ca2+-induced nonspecific
mitochondrial permeability transition pores (mPTP) opening
in the heart of old rats were studied. Changes in biochemical
parameters characterizing the intensity of oxidative processes
in organelles at the action of glutathione were also studied.
The expression levels of Kir6.1 і Kir6.2 subunits KATP
channels were determined using reverse transcription and
quantitative PCR. It was shown that after the administration
of glutathione to old rats, the expression of KATP channel
subunits significantly increased, namely for Kir6.1 9.3 times,
for Kir6.2 2.6 times.
The use of glutathione in older animals
inhibited mPTP opening: reduced the amplitude of spontaneous and Ca2+-induced swelling of mitochondria. An important
consequence of the action of glutathione during aging was a
decrease in the rate of generation of superoxide (.О2-) and
hydroxyl (.ОН) radicals, as well as the content of hydrogen
peroxide respectively in 1.8, 2.5 and 3.2 times compared with
these figures in older animals without treatment. Glutathione
also reduced lipid peroxidation, particularly pools of diene
conjugates (2.5-fold) and malonic dialdehyde (1.8-fold). Thus,
glutathione significantly increases the expression of KCNJ8
and KCNJ11 genes encoding Kir6.1 and Kir6.2 subunits of
KATP channels in the heart of rats, regulates MP, preventing its
opening, and reduces oxidative stress, indicating its important
role in myocardial protection.
Keywords:
glutathione; expression of Kir6.1 and Kir6.2; KATP channels; oxidative stress; aging; mitochondria; heart; rats
References
- Bellezza I, Riuzzi F, Chiappalupi S, Arcuri C, Giambanco I, Sorci G, Donato R. Reductive stress in striated muscle cells. Cell Mol Life Sci. 2020 Sep;77(18):3547-65.
CrossRef
PubMed
- Maher P. The effects of stress and aging on glutathione metabolism. Ageing Res Rev, 2005;4:288-314.
CrossRef
PubMed
- Homma T, Fujii J. Application of glutathione as antioxidative and anti-aging drugs. Curr Drug Metab. 2015;16(7):560-71.
CrossRef
PubMed
- Liu R, Choi J. Age-associated decline in gamma-glutamylcysteine synthetase gene expression in rats. Free Radic Biol Med. 2000; 28:566-74.
CrossRef
- Sekhar RV, Patel SG, Guthikonda AP, Reid M, Balasubramanyam A, Taffet GE, Jahoor F. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr. 2011 Sep;94(3):847-53.
CrossRef
PubMed PubMedCentral
- Ranki HJ, Crawford RM, Budas GR, Jovanović A. Ageing is associated with decrease in number of sarcolemmal ATP-sensitive K+ channels in a gender-dependent manner. Mech. Ageing Dev. 2002. 123:695-705.
CrossRef
- Sudhir R, Sukhodub A, Du Q, Jovanović S, Jovanović A. Ageing-induced decline in physical endurance in mice is associated with decrease in cardiac SUR2A and increase in cardiac susceptibility to metabolic stress: therapeutic prospects for up-regulation of SUR2A. Biogerontology. 2011; 12(2):147-55.
CrossRef
PubMed
- Strutynskyi RB. Protective properties of opening ATPsensitive potassium channels. Fiziol Zh. 2019;65(3):74-86. [Ukrainian].
CrossRef
- Ngo AT, Riemann M, Holstein-Rathlou NH, Torp-Pedersen C, Jensen LJ. Significance of K(ATP) channels, L-type Ca²⁺ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo. BMC Physiol. 2013 May 12;13-8.
CrossRef
PubMed PubMedCentral
- Strutyns'kyĭ RB, Kotsiuruba AV, Rovenets' RA, Strutyns'ka NA, Iagupols'kyĭ IuL, Sagach VF, Moĭbenko OO. Biochemical mechanisms of the cardioprotective effect of the K(ATP) channels opener flocalin (medicinal form) in ischemia-reperfusion of myocardium. Fiziol Zh. 2013;59(4):16-27. [Ukrainian].
- Crawford RM, Jovanović S, Budas GR, Davies AM, Lad H, Wenger RH, Robertson KA, Roy DJ, Ranki HJ, Jovanović A. Chronic mild hypoxia protects heart-derived H9c2 cells against acute hypoxia/reoxygenation by regulating expression of the SUR2A subunit of the ATPsensitive K+ channels. J Biol Chem. 2003; 278:31444-55.
CrossRef
PubMed PubMedCentral
- Du Q, Jovanović S, Clelland A, Sukhodub A, Budas G, Phelan K, Murray-Tait V, Malone L, Jovanović A. Overexpression of SUR2A generates a cardiac phenotype resistant to ischemia FASEB J. 2006; 20(8): 1131-41.
CrossRef
PubMed PubMedCentral
- Shi W, Cui N, Wu Z, Yang Y, Zhang S, Gai H, Zhu D, Jiang C. Lipopolysaccharides up-regulate Kir6.1/SUR2B channel expression and enhance vascular KATP channel activity via NF-kappa B-dependent signaling. J Biol Chem. 2010 Jan 29;285(5):3021-9. 14. Zhao Y, Ge J, Li X, Guo Q, Zhu Y, Song J, Zhang L, Ding S, Yang X, Li R. Vasodilatory effect of formaldehyde via the NO/cGMP pathway and the regulation of expression of KATP, BKCa and L-type Ca2+ channels. Toxicol Lett. 2019; Sep 15;312:55-64.
CrossRef
PubMed
- Sun Y, Huang Y, Zhang R, Chen Q, Chen J, Zong Y, Liu J, Feng S, Liu AD, Holmberg L, Liu D, Tang C, Du J, Jin H. Hydrogen sulfide upregulates KATP channel expression in vascular smooth muscle cells of spontaneously hypertensive rats. J Mol Med (Berl). 2015 Apr;93(4):439-55.
CrossRef
PubMed
- Strutyns'kyĭ RB, Kotsiuruba AV, Neshcheret OP, Rovenets' RA, Moĭbenko OO. The changes of metabolism in myocardium at ischemia-reperfusion and activating of the ATP-sensitive potassium channels. Fiziol Zh. 2012;58(1):13-26. [Ukrainian].
CrossRef
PubMed
- Strutynskyi RB, Moybenko OO, Chebanov VA, Gorobets NY. Modeling of production industrial process of the drug flocalin and search of its optimally effective dose for treatment of heart diseases. Nauka Innov. 2013; 9 (1):55-63. [Ukrainian].
CrossRef
- De Flora S, Balansky R, and La Maestra S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB J. 2020; 34: 13185-93.
CrossRef
PubMed PubMedCentral
- Sestili P, Fimognari C. Paracetamol-induced glutathione consumption: is there a link with severe COVID-19 illness? Front Pharmacol. 2020 Oct 7;11:579944.
CrossRef
PubMed PubMedCentral
- Strutynska NA, Kotsiuruba AV, Budko AYu, Mys LA, Sagach VF. Mitochondrial dysfunction in the aging heart is accompanied by constitutive no-synthases uncoupling on the background of oxidative and nitrosative stress. Fiziol Zh. 2016; 62(2):3-11. [Ukrainian].
CrossRef
- Kwong J, Molkentin J. Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab. 2015;21(2):206-14.
CrossRef
PubMed PubMedCentral
- Strutynska NA, Semenykhina OM, Chorna SV, Vavilova GL, Sagach VF. Hydrogen sulphide inhibits Ca2+-induced mitochondrial permeability transition pore opening in adult and old rat heart. Fiziol Zh. 2011;57(6):3-13. [Ukrainian].
CrossRef
- Mys LA, Strutynska NA, Strutynskyi VR, Sagach VF. Activation of endogenous hydrogen sulphide synthesis inhibits mitochondrial permeability transition pore opening and restores constitutive no-synthase coupling in old rat hearts. Fiziol Zh. 2017; 63(3):16-23. [Ukrainian].
- Kharechkina ES, Nikiforova AB, Kruglov AG. Pyridine nucleotides regulate the superoxide anion flash upon permeabilization of mitochondrial membranes: An MCLA-based study. Free Radic Biol Med. 2018 Aug 20; 124:473-83.
CrossRef
PubMed
- Vercesi AE, Castilho RF, Kowaltowski AJ, de Oliveira HCF, de Souza-Pinto NC, Figueira TR, Busanello ENB. Mitochondrial calcium transport and the redox nature of the calcium-induced membrane permeability transition Free Radic Biol Med. 2018 Dec;129:1-24.
CrossRef
PubMed
|