Naringin prevents heart mitochondria dysfunction during diabetic cardiomyopathy in rats: Original scientific article

Ilya Zavodnik; Tatsiana A.  Kavalenia; Siarhei N.  Kirko; Elena B.  Belonovskaya; Irina A. Kuzmitskaya; Yulia V. Eroshenko; Elena A. Lapshina; Vyacheslav U.  Buko

doi:10.5599/admet.2571

Authors

Ilya Zavodnik Department of Biochemistry, Yanka Kupala State University of Grodno, Bulvar Leninskogo Komsomola, 5, 230009 Grodno, Grodno, Belarus https://orcid.org/0000-0002-6130-787X
Tatsiana A. Kavalenia Department of Biochemistry, Yanka Kupala State University of Grodno, Bulvar Leninskogo Komsomola, 5, 230009 Grodno, Grodno, Belarus https://orcid.org/0009-0003-5458-3774
Siarhei N. Kirko Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Bulvar Leninskogo Komsomola, 50, 230030 Grodno, Belarus https://orcid.org/0000-0002-6573-3139
Elena B. Belonovskaya Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Bulvar Leninskogo Komsomola, 50, 230030 Grodno, Belarus https://orcid.org/0000-0002-8354-4606
Irina A. Kuzmitskaya Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Bulvar Leninskogo Komsomola, 50, 230030 Grodno, Belarus https://orcid.org/0009-0001-6362-5679
Yulia V. Eroshenko Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Bulvar Leninskogo Komsomola, 50, 230030 Grodno, Belarus https://orcid.org/0009-0002-6238-601X
Elena A. Lapshina Department of Biochemistry, Yanka Kupala State University of Grodno, Bulvar Leninskogo Komsomola, 5, 230009 Grodno, Grodno, Belarus https://orcid.org/0000-0002-6130-787X
Vyacheslav U. Buko Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Bulvar Leninskogo Komsomola, 50, 230030 Grodno, Belarus https://orcid.org/0000-0001-5638-1314

DOI:

https://doi.org/10.5599/admet.2571

Keywords:

Cardiac mitochondria, flavonoids, respiration, islets

Abstract

Background and purpose: Cardiac mitochondria dysfunction plays a central pathophysiological role in the abnormal glucose metabolism in the heart and in diabetic cardiomyopathy. The present study evaluated the effects of flavonoid glycoside naringin treatment on the interconnection between changes in cardiac mitochondria oxygen consumption, membrane potential and mitochondrial Ca²⁺ sensitivity during type 1 diabetes. Experimental approach: Type 1 diabetes was induced by an intraperitoneal injection of streptozotocin (40 mg/kg) in rats and islet morphology, glucose and insulin levels, changes in heart mitochondria respiration, membrane potential, spontaneous and Ca²⁺ - induced mitochondrial permeability transition (MPT) pore opening were evaluated. Key results: Diabetes resulted in typical signs of hyperglycemia, which were accompanied by a rat cardiac mitochondria dysfunction, manifested by decreased V₂ and V₃ rates of oxygen consumption, while the initial membrane potential value remained unchanged. The rates of Ca²⁺-induced MPT pore opening and Ca²⁺-induced membrane potential dissipation in isolated mitochondria decreased under type 1 diabetes. The naringin treatment (40 mg/kg of the body weight, 4 weeks) partially recovered impaired cardiac mitochondria respiration, decreased spontaneous and increased Ca²⁺-induced MPT pore opening, improved pancreatic islets morphology and dystrophic changes, lowered glycated hemoglobin and blood plasma urea, and decreased the oxidative stress level with glucose or insulin concentrations remaining unchanged in diabetic animals. Conclusions: Naringin administration demonstrated beneficial effects during type 1 diabetes and represents a promising therapeutic (or nutriceutical) approach for diabetes treatment.

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References

P. Rosen, P.P. Nawroth, G. King, W. Möller, H.J. Tritschler, L. Packer. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes/Metabolism Research and Reviews 17 (2001) 189-212. https://doi.org/10.1002/dmrr.196

H. Bugger, E.D. Abel. Mitochondria in the diabetic heart. Cardiovascular Research 88 (2010) 229-240. https://doi.org/10.1093/cvr/cvq239

G. Borghetti, D. von Lewinski, D.M. Eaton, H. Sourij, S.R. Houser, M. Wallner. Diabetic cardiomyopathy: current and future therapies. Beyond glycemic control. Frontiers in Physiology 9 (2018) 1514. https://doi.org/10.3389/fphys.2018.01514

G. Jia, M.A. Hill, J.R. Sowers. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circulation Research 122 (2018) 624-638. https://doi.org/10.1161/CIRCRESAHA.117.311586

R. Marfella, C. Sardu, G. Mansueto, C. Napoli, G. Paolisso. Evidence for human diabetic cardiomyopathy. Acta Diabetologica 58 (2021) 983-988. https://doi.org/10.1007/s00592-021-01705-x

G. Jia, V.G. DeMarco, J.R. Sowers. Insulin resistance and hyperinsulinaemia in diabetic cardio¬myo-pathy. Nature Reviews. Endocrinology 12 (2016) 144-153. https://doi.org/10.1038/nrendo.2015.216

S.H. Kwak, K.S. Park, K.U. Lee, H.K. Lee. Mitochondrial metabolism and diabetes. Journal of Diabetes Investigation 1 (2010) 161-169. https://doi.org/10.1111/j.2040-1124.2010.00047.x

H. Bugger, E.D. Abel. Rodent models of diabetic cardiomyopathy. Disease Models & Mechanisms 2 (2009) 454-466. https://doi.org/10.1242/dmm.001941

M. Diamant, H.J. Lamb, Y. Groeneveld, E.L. Endert, J.W.A. Smit, J.J. Bax, J.A. Romijn, A. de Roos, J.K. Radder. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. Journal of the American College of Cardiology 42 (2003) 328-335. https://doi.org/10.1016/s0735-1097(03)00625-9

N. Krako Jakovljević, K. Pavlović, A. Jotić, K. Lalić, M. Stoiljković, L. Lukić, T. Miličić, M. Macesić, J. Stanarčić Gajović, N.M. Lalić. Targeting Mitochondria in Diabetes. International Journal of Molecular Sciences 22 (2021) 6642. https://doi.org/10.3390/ijms22126642

M. Scheuermann-Freestone, P.L. Madsen, D. Manners, A.M. Blamire, R.E. Buckingham, P. Styles, G.K. Radda, S. Neubauer, K. Clarke. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 107 (2003) 3040-3046. https://doi.org/10.1161/01.CIR.0000072789.89096.10

L.K. Gerber, B.J. Aronow, M.A. Matlib. Activation of a novel long-chain free fatty acid generation and export system in mitochondria of diabetic rat hearts. American Journal of Physiology-Cell Physiology 291 (2006) 1198-1207. https://doi.org/10.1152/ajpcell.00246.2006

V.K. Mootha, C. Handschin, D. Arlow, X. Xie, J.St. Pierre, S. Sihag, W. Yang, D. Altshuler, P. Puigserver, N. Patterson, P.J. Willy, I.G. Schulman, R.A. Heyman, E.S. Lander, B.M. Spiegelman. Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proceedings of the National Academy of Sciences of the United States of America 101 (2004) 6570-6575. https://doi.org/10.1073/pnas.0401401101

P. Prasun. Role of mitochondria in pathogenesis of type 2 diabetes mellitus. Journal of Diabetes & Metabolic Disorders 19 (2020) 2017-2022. https://doi.org/10.1007/s40200-020-00679-x

M. Anello, R. Lupi, D. Spampinato, S. Piro, M. Masini, U. Boggi, S. Del Prato, A.M. Rabuazzo, F. Purrello, P. Marchetti. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48 (2005) 282-289. https://doi.org/10.1007/s00125-004-1627-9

H. Huang, K. Wu, Q. You, R. Huang, S. Li, K. Wu. Naringin inhibits high glucose-induced cardiomyocyte apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway. International Journal of Molecular Medicine 32 (2013) 396-402. https://doi.org/10.3892/ijmm.2013.1403

Y. Peng, R. Qu, Sh. Xu, H. Bi, D. Guo. Regulatory mechanism and therapeutic potentials of naringin against inflammatory disorders. Heliyon 10 (2024) e24619. https://doi.org/10.1016/j.heliyon.2024.e24619

C. Felgines, O. Texier, C. Morand, C. Manach, A. Scalbert, F. Régerat, C. Rémésy. Bioavailability of the flavanone naringenin and its glycosides in rats. American Journal of Physiology - Gastrointestinal and Liver Physiology 279 (2000) G1148-G1154. https://doi.org/10.1152/ajpgi.2000.279.6.G1148

A. Uryash, A. Mijares, V. Flores, J.A. Adams, J.R. Lopez. Effects of naringin on cardiomyocytes from a rodent model of type 2 diabetes. Frontiers in Pharmacology 12 (2021) 719268. https://doi.org/10.3389/fphar.2021.719268

A. Pérez, J. Mukdsi, L. Valdez, I. Rukavina-Mikusić, G. Díaz de Barboza, N. Tolosa de Talamoni, M. Rivoira. Naringin prevents diabetic nephropathy in rats through blockage of oxidative stress and attenuation of the mitochondrial dysfunction. Canadian Journal of Physiology and Pharmacology 101 (2023) 349-360. https://doi.org/10.1139/cjpp-2022-0449

National Research Council US, Guide for the Care and Use of Laboratory Animals, National Academies Press, Washington, 2011, p. 246. https://nap.nationalacademies.org/read/12910/chapter/3

D. Johnson, H.A. Lardy. Isolation of liver or kidney mitochondria. Methods in Enzymology 10 (1967) 94-96. https://doi.org/10.1016/0076-6879(67)10018-9

I. Gostimskaya, A. Galkin. Preparation of highly coupled rat heart mitochondria. Journal of Visualized Experiments : JoVE 23 (2010) 2202. https://doi.org/10.3791/2202

O.H. Lowry, N.J. Rosebrough, A.L. Farr, R.J. Randall. Protein measurement with the Folin phenol reagent. The Journal of Biological Chemistry 193 (1951) 265-275. https://doi.org/10.1016/s0021-9258(19)52451-6

E.R. Weibel. Principles and methods for the morphometric study of the lung and other organ. Laboratory Investigation; a Journal of Technical Methods and Pathology 12 (1963) 131-155.

M.A. Williams, Quantitative Methods in Biology, V. 6. Practical methods in electron microscopy, North Holland, Amsterdam, Netherlands, 1977, pp. 48–62.

K.E. Akerman, M.K. Wikström. Safranine as a probe of the mitochondrial membrane potential. FEBS Letters 68 (1976) 191-197. https://doi.org/10.1016/0014-5793(76)80434-6

A.L. Moore, W.D. Bonner. Measurements of membrane potentials in plant mitochondria with the safranine method. Plant Physiology 70 (1982) 1271-1276. https://doi.org/10.1104/pp.70.5.1271

T.A. Kavalenia, E.A. Lapshina, T.V. Ilyich, Hu‑Cheng Zhao, I.B. Zavodnik. Functional activity and morphology of isolated rat cardiac mitochondria under calcium overload. Effect of naringin. Molecular and Cellular Biochemistry 479 (2024) 3329-3340. https://doi.org/10.1007/s11010-024-04935-z

J. Stocks, T.L. Dormandy. The autoxidation of human red cell lipids induced by hydrogen peroxide. British Journal of Haematology 20 (1971) 95-111. https://doi.org/10.1111/j.1365-2141.1971.tb00790.x

G.J. Ellman. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics 82 (1959) 70-77. https://doi.org/10.1016/0003-9861(59)90090-6

J.I.R. Martinez, J.M. Launay, C. Dreux. A sensitive fluorimetric microassay for the determination of glutathione peroxidase activity. Application to human blood platelets. Analytical Biochemistry 98 (1979) 154-159. https://doi.org/10.1016/0003-2697(79)90720-6

N.A. Calcutt, M.E. Cooper, T.S. Kern, A.M. Schmidt. Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nature Reviews Drug Discovery 8 (2009) 417-429. https://doi.org/10.1038/nrd2476

M.V. Pinti, G.K. Fink, Q.A. Hathaway, A.J. Durr, A. Kunovac, J.M. Hollander. Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis. American Journal of Physiology - Endocrinology and Metabolism 316 (2019) E268-E285. https://doi.org/10.1152/ajpendo.00314.2018

E.J. Anderson, A.P. Kypson, E. Rodriguez, C.A. Anderson, E.J. Lehr, P.D. Neufer. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. Journal of the American College of Cardiology 54 (2009) 1891-1898. https://doi.org/10.1016/j.jacc.2009.07.031

E.J. Anderson, E. Rodriguez, C.A. Anderson, K. Thayne, W.R. Chitwood, A.P. Kypson. Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways. American Journal of Physiology - Heart and Circulatory Physiology 300 (2011) H118-H124. https://doi.org/10.1152/ajpheart.00932.2010

A. Sorrentino, G. Borghetti, Y. Zhou, A. Cannata, M. Meo, S. Signore, P. Anversa, A. Leri, P. Goichberg, K. Qanud, J.T. Jacobson, T.H. Hintze, M. Rota. Hyperglycemia induces defective Ca2+ homeostasis in cardiomyocytes. American Journal of Physiology. Heart and Circulatory Physiology 312 (2017) H150-H161. https://doi.org/10.1152/ajpheart.00737.2016

F.R. Prandi, I. Evangelista, D. Sergi, A. Palazzuoli, F. Romeo. Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants. Heart Failure Reviews 28 (2023) 597-606. https://doi.org/10.1007/s10741-021-10200-y

H. Bugger, S. Boudina, X.X. Hu, J. Tuinei, V.G. Zaha, H.A. Theobald, U.J. Yun, A.P. McQueen, B. Wayment, S.E. Litwin, E.D. Abel. Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes 57 (2008) 2924-2932. https://doi.org/10.2337/db08-0079

F. Marino, N. Salerno, M. Scalise, L. Salerno, A. Torella, C. Molinaro, A. Chiefalo, A. Filardo, C. Siracusa, G. Panuccio, C. Ferravante, G. Giurato, F. Rizzo, M. Torella, M. Donniacuo, A. De Angelis, G. Viglietto, K. Urbanek, A. Weisz, D. Torella, E. Cianflone. Streptozotocin-induced type 1 and 2 diabetes mellitus mouse models show different functional, cellular and molecular patterns of diabetic cardiomyopathy. International Journal of Molecular Sciences 24 (2023) 1132. https://doi.org/10.3390/ijms24021132

J.A. Herlein, B.D. Fink, Y. O'Malley, W.I. Sivitz. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology 150 (2009) 46-55. https://doi.org/10.1210/en.2008-0404

I. Sadowska-Bartosz, G. Bartosz. Prevention of protein glycation by natural compounds. Molecules 20 (2015) 3309-3334. https://doi.org/10.3390/molecules20023309

E.E. Mulvihill, E.M. Allister, B.G. Sutherland, D.E. Telford, C.G. Sawyez, J.Y. Edwards, J.M. Markle, R.A. Hegele, M.W. Huff. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes 58 (2009) 2198-2210. https://doi.org/10.2337/db09-0634

T. Annadurai, A.R. Muralidharan, T. Joseph, M.J. Hsu, P.A. Thomas, P. Geraldine. Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin–nicotinamide-induced experimental diabetic rats. Journal of Physiology and Biochemistry 68 (2012) 307-318. https://doi.org/10.1007/s13105-011-0142-y

J.S. Choi, T. Yokozawa, H. Oura. Improvement of hyperglycemia and hyperlipemia in streptozotocin-diabetic rats by a methanolic extract of Prunus davidiana stems and its main component, prunin. Planta Medica 57 (1991) 208-211. https://doi.org/10.1055/s-2006-960075

V. Buko, I. Zavodnik, O. Kanuka, E. Belonovskaya, E. Naruta, O. Lukivskaya, S. Kirko, G. Budryn, D. Żyżelewicz, J. Oracze, N. Sybirna. Antidiabetic effects and erythrocyte stabilization by red cabbage extract in streptozotocin-treated rats. Food & Function 9 (2018) 1850-1863. https://doi.org/10.1039/c7fo01823a

X. Shen, S. Zheng, V. Thongboonkerd, M. Xu, W.M.Jr. Pierce, J.B. Klein, P.N. Epstein. Cardiac mitochondrial damage and biogenesis in a chronic model of type 1 diabetes. American Journal of Physiology - Endocrinology and Metabolism 287 (2004) E896-905. https://doi.org/10.1152/ajpendo.00047.2004

A. Riojas-Hernández, J. Bernal-Ramírez, D. Rodríguez-Mier, F.E. Morales-Marroquín, E.M. Domínguez-Barragán, C. Borja-Villa, I. Rivera-Álvarez, G. García-Rivas, J. Altamirano, N. García. Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker Fa/fa rats with type 2 diabetes. Life Sciences 141 (2015) 32-43. https://doi.org/10.1016/j.lfs.2015.09.018

V.P.M. van Empel, A.T.A. Bertrand, L. Hofstra, H.J. Crijns, P.A. Doevendans, L.J. De Windt. Myocyte apoptosis in heart failure. Cardiovascular Research 67 (2005) 21-29. https://doi.org/10.1016/j.cardiores.2005.04.012

L. Cai, Y.J. Kang. Cell death and diabetic cardiomyopathy. Cardiovascular Toxicology 3 (2003) 219-228. https://doi.org/10.1385/CT:3:3:219

V. Rodríguez, L. Plavnik, N.T. de Talamoni. Naringin attenuates liver damage in streptozotocin-induced diabetic rats. Biomedicine & Pharmacotherapy 105 (2018) 95-102. https://doi.org/10.1016/j.biopha.2018.05.120

Z. Yuan, Z. Yang. The effect of naringin on the apoptosis of degenerative nucleus pulposus cells: a study on the function and mechanism. Drug Design, Development and Therapy 16 (2022) 499-508. https://doi.org/10.2147/DDDT.S338355

H. Wang, Y.S. Xu, M.L. Wang, C. Cheng, R. Bian, H. Yuan, Y. Wang, T. Guo, L.L. Zhu, H. Zhou. Protective effect of naringin against the LPS-induced apoptosis of PC12 cells: Implications for the treatment of neurodegenerative disorders. International Journal of Molecular Medicine 39 (2017) 819-830. https://doi.org/10.3892/ijmm.2017.2904

C. Xu, X. Huang, Y. Huang, X. Liu, M. Wu, J. Wang, X. Duan. Naringin induces apoptosis of gastric carcinoma cells via blocking the PI3K/AKT pathway and activating pro death autophagy. Molecular Medicine Reports 24 (2021) 772. https://doi.org/10.3892/mmr.2021.12412

G. Han, D.G. Lee. Naringin generates three types of reactive oxygen species contributing differently to apoptosis-like death in Escherichia coli. Life Sciences 304 (2022) 120700. https://doi.org/10.1016/j.lfs.2022.120700