Ovariektomize Sıçanlarda Liraglutid’in Kalp Fonksiyonları Üzerine Etkisi

Year 2022, , 1 - 9, 30.04.2022

İnci Turan , Candan Sağlam Salih Erdem , Hale Sayan Özaçmak

https://doi.org/10.25048/tudod.1074076

Cited By: 1

Abstract

Amaç: Glukagon benzeri peptit-1 (GLP-1), enteroendokrin L hücrelerinden salgılanan önemli bir inkretin hormondur. GLP-1 analogları,
diyabet ve obezite tedavisi için kullanılmaktadır. Ovaryan hormonların kardiyovasküler fonksiyonların düzenlenmesinde etkili rol
oynadığı iyi bilinmektedir. Postmenopozal kadınlarda kardiyovasküler hastalık insidansı artar. Bu çalışmanın amacı, yumurtalıkları
alınmış sıçanlarda GLP- 1 analoğu olan liraglutid uygulanmasının kardiyak fonksiyonlar ve kalp dokusu oksidatif stres üzerindeki
etkisini araştırmaktır.
Gereç ve Yöntemler: Çalışmada otuz iki genç dişi Wistar albino sıçan kullanıldı. Denekler rastgele kontrol, liraglutid ile tedavi edilen
kontrol, yumurtalıkları alınan (OVX) ve liraglutid ile tedavi edilen OVX gruplarına ayrıldı. İki aylık dişi sıçanlarda ovariektomi ve sahte
cerrahi işlemler uygulandı. Ovariektomi operasyonundan beş hafta sonra liraglutid tedavisi (150μg/kg, deri altı, 14 gün) başlandı. 14
günlük süre sonunda kalp atım hızı ve kan basıncı ölçümleri yapıldıktan sonra hayvanlar sakrifiye edildi, kahverengi ve beyaz yağ dokusu
ağırlıkları ile kalp dokusu malondialdehit (MDA), indirgenmiş glutatyon (GSH), nitrat, glikojen ve askorbik asit seviyeleri ölçüldü.
Bulgular: Kalp hızı açısından tüm gruplar arasında fark bulunmazken, liraglutid uygulanan gruplarda kan basıncı istatistiksel olarak
anlamlı derecede azaldı. MDA ve askorbik asit seviyeleri tüm gruplar arasında önemli bir değişim gözlenmedi. GSH seviyeleri liraglutid
ile tedavi edilen OVX grubunda arttı. Ovariektomi ile kalp dokusunda nitrat düzeylerinin azaldığı saptandı. Kardiyak glikojen düzeyi
OVX ve liraglutid uygulanan OVX grubunda kontrol grubuna göre artmış olarak bulunmuştur. Liraglutid tedavisi kalpteki nitrat
miktarını kontrol seviyelerinde korudu. Ek olarak, liraglutid uygulaması OVX sıçanlarında retroperitoneal yağ birikimini azalttı.
Sonuç: Sonuçlarımız GLP-1 uygulamasının ovariektominin neden olduğu kan basıncı artışı ve kalp dokusunda azalan GSH seviyelerini
korumada etkili olduğu bulunmuştur. Bu nedenle, GLP-1 analogları, postmenopozal dönemde kan basıncının düzenlenmesinde
potansiyel terapötik ajan olarak kabul edilebilir.

Keywords

GLP-1, Ovarektomi, Oksidatif stres, Kalp

Supporting Institution

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Project Number

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Thanks

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The Effect of Liraglutide on Cardiac Functions in Ovariectomized Rats

Abstract

Aim: Glucagon-like peptide 1 (GLP-1) is an important incretin hormone secreted from enteroendocrine L cells. GLP-1 analogs are
used for the treatment of diabetes and obesity. Ovarian hormones are well known in playing critical roles in regulating cardiovascular
functions. Cardiovascular disease incidence increases in postmenopausal women. The aim of this study was to investigate the effect of
administration of liraglutide, a GLP 1 analogue, on cardiac function and cardiac tissue oxidative stress in ovariectomized rats.
Material and Methods: Thirty two young female Wistar albino rats were used in the study. Subjects were randomly divided into control,
liraglutide-treated control, ovariectomized (OVX), and liraglutide-treated OVX groups. Ovariectomy and sham surgical procedures were
performed in 2-month-old female rats. Liraglutide treatment (150μg/kg, subcutaneous, 14 days) was started five weeks after the ovariectomy
operation. After measuring the heart rate and blood pressure at the end of the 14-day period, the animals were sacrificed, brown and white
adipose tissue weights, and heart tissue malondialdehyde (MDA), reduced glutathione (GSH), nitrate, glycogen and ascorbic acid levels
were measured.
Results: While there was no difference between all groups in terms of heart rate, blood pressure was statistically significantly decreased
in the liraglutide-administered groups. MDA and ascorbic acid levels did not change significantly between all groups. GSH levels
were increased in the liraglutide-treated OVX group. It was found that the cardiac glycogen level was increased in the OVX group
treated with OVX and liraglutide compared to the control group. Nitral levels in the heart tissue were found to be decreased with
ovarectomy. Liraglutide treatment maintained nitrate levels in the heart at control levels. In addition, liraglutide administration reduced
retroperitoneal fat deposition in OVX rats.
Conclusion: Our results showed that GLP-1 administration was effective in reducing the increased blood pressure due to ovariectomy
and maintaining the decreased GSH level in the heart tissue.. Therefore, GLP-1 analogs can be considered as potential therapeutic agents
in the regulation of blood pressure in the postmenopausal period.

Keywords

GLP-1, Ovariectomy, Oxidative stress, Heart

Project Number

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References

• 1. de Fátima Laureano Martins J, Souza-Silva TG, Paula HAA, Rafael VDC, Sartori SSR, Ferreira CLLF. Yacon-based product improves intestinal hypertrophy and modulates the production of glucagon-like peptide-1 in postmenopausal experimental model. Life Sci. 2022;291:120245.
• 2. Marinho PM, Salomon TB, Andrade AS, Behling CS, Putti JS, Benfato MS, Hackenhaar FS. The effect of n-3 long-chain polyunsaturated fatty acids and lipoic acid on the heart in the ovariectomized rat model of menopause. Free Radic Res. 2019;53(6):669-679.
• 3. Yang XP, Reckelhoff JF. Estrogen, hormonal replacement therapy and cardiovascular disease. Curr Opin Nephrol Hypertens. 2011;20:133-138.
• 4. Prokai-Tatrai K, Perjesi P, Rivera-Portalatin NM, Simpkins JW, Prokai L. Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative. Steroids. 2008;73(3):280-288.
• 5. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931- 947.
• 6.Castardo-de-Paula JC, de Campos BH, Amorim EDT, da Silva RV, de Farias CC, Higachi L, Pinge-Filho P, Barbosa DS, Martins-Pinge MC. Cardiovascular risk and the effect of nitric oxide synthase inhibition in female rats: The role of estrogen. Exp Gerontol. 2017;97:38-48.
• 7. Knowlton AA, Lee AR. Estrogen and the cardiovascular system. Pharmacol Ther. 2012;135(1):54-70.
• 8. Phungphong S, Kijtawornrat A, Wattanapermpool J, Bupha- Intr T. Improvement in cardiac function of ovariectomized rats by antioxidant tempol. Free Radic Biol Med. 2020;160:239- 245.
• 9. Rutter MK, Parise H, Benjamin EJ, Levy D, Larson MG, Meigs JB, Nesto RW, Wilson PW, Vasan RS. Impact of glucose intolerance and insulin resistance on cardiac structure and function: Sex-related differences in the Framingham Heart Study. Circulation. 2003;107(3):448-454.
• 10. Bhuiyan MS, Fukunaga K. Characterization of an animal model of postmenopausal cardiac hypertrophy and novel mechanisms responsible for cardiac decompensation using ovariectomized pressure-overloaded rats. Menopause. 2010;17:213-221.
• 11. Shi N, He J, Guo Q, Liu T, Han J. Liraglutide protects against diabetes mellitus complicated with focal cerebral ischemic injury by activating mitochondrial ATP-sensitive potassium channels. Neuroreport. 2019;30(7):479-484.
• 12. Hölscher C. Central effects of GLP-1: New opportunities for treatments of neurodegenerative diseases. J Endocrinol. 2014;221:T31.
• 13. Yaribeygi H, Farrokhi FR, Abdalla MA, Sathyapalan T, Banach M, Jamialahmadi T, Sahebkar A. The effects of glucagonlike peptide-1 receptor agonists and dipeptydilpeptidase-4 inhibitors on blood pressure and cardiovascular complications in diabetes. J Diabetes Res. 202;2021:6518221.
• 14. Deng C, Cao J, Han J, Li J, Li Z, Shi N, He J. Liraglutide activates the Nrf2/HO-1 antioxidant pathway and protects brain nerve cells against cerebral ischemia in diabetic rats. Comput Intell Neurosci. 2018;2018:3094504.
• 15. Hu SY, Zhang Y, Zhu PJ, Zhou H, Chen YD. Liraglutide directly protects cardiomyocytes against reperfusion injury possibly via modulation of intracellular calcium homeostasis. J Geriatr Cardiol. 2017;14(1):57-66.
• 16. Chen WR, Hu SY, Chen YD, Zhang Y, Qian G, Wang J, Yang JJ, Wang ZF, Tian F, Ning QX. Effects of liraglutide on left ventricular function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am Heart J. 2015;170(5):845-854.
• 17. Eid RA, Bin-Meferij MM, El-Kott AF, Eleawa SM, Zaki MSA, Al-Shraim M, El-Sayed F, Eldeen MA, Alkhateeb MA, Alharbi SA, Aldera H, Khalil MA. Exendin-4 protects against myocardial ischemia-reperfusion injury by upregulation of SIRT1 and SIRT3 and activation of AMPK. J Cardiovasc Transl Res. 2021;14(4):619-635.
• 18. Yin W, Borniger JC, Wang X, Maguire SM, Munselle ML, Bezner KS, Tesfamariam HM, Garcia AN, Hofmann HA, Nelson RJ, Gore AC. Estradiol treatment improves biological rhythms in a preclinical rat model of menopause. Neurobiol Aging. 2019;83:1-10.
• 19. Barthem CS, Rossetti CL, Carvalho DP, da-Silva WS. Metformin ameliorates body mass gain and early metabolic changes in ovariectomized rats. Endocr Connect. 2019;8(12):1568-1578.
• 20. Model JFA, Lima MV, Ohlweiler R, Lopes Vogt É, Rocha DS, Souza SK, Türck P, Araújo ASDR, Vinagre AS. Liraglutide improves lipid and carbohydrate metabolism of ovariectomized rats. Mol Cell Endocrinol. 2021;524:111158.
• 21. Kim JH, Cho HT, Kim YJ. The role of estrogen in adipose tissue metabolism: Insights into glucose homeostasis regulation. Endocr J. 2014;61(11):1055-1067.
• 22. Casini AF, Ferrali M, Pompella A, Maellaro E, Comporti M. Lipid peroxidation and cellular damage in extrahepatic tissues of bromobenzene-intoxicated mice. Am J Pathol. 1986;123(3):520-531.
• 23. Aykac G, Uysal M, Yalçın AS, Kocak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology. 1986;36:71-76.
• 24. Miranda KM, Espey MG, Wink DA. A rapid simple spectrofotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5(1):62-71.
• 25. Berger J, Shepard D, Morrow F, Taylor A. Relationship between dietary intake and tissue levels of reduced and total vitamin C in the nonscorbutic guinea pig. J Nutr. 1989;119:734-740.
• 26. Bendale DS, Karpe PA, Chhabra R, Shete SP, Shah H, Tikoo K. 17-β Oestradiol prevents cardiovascular dysfunction in postmenopausal metabolic syndrome by affecting SIRT1/AMPK/ H3 acetylation. Br J Pharmacol. 2013;170(4):779-795.
• 27. Woo JS, Kim W, Ha SJ, Kim JB, Kim SJ, Kim WS, Seon HJ, Kim KS. Cardioprotective effects of exenatide in patients with STsegment- elevation myocardial infarction undergoing primary percutaneous coronary intervention: Results of exenatide myocardial protection in revascularization study. Arterioscler Thromb Vasc Biol. 2013;33(9):2252-2260.
• 28. Gortan Cappellari G, Losurdo P, Mazzucco S, Panizon E, Jevnicar M, Macaluso L, Fabris B, Barazzoni R, Biolo G, Carretta R, Zanetti M. Treatment with n-3 polyunsaturated fatty acids reverses endothelial dysfunction and oxidative stress in experimental menopause. J Nutr Biochem. 2013;24(1):371- 379.
• 29. Wu H, Xiao C, Zhao Y, Yin H, Yu M. Liraglutide Improves Endothelial Function via the mTOR Signaling Pathway. J Diabetes Res. 2021;2021:2936667.
• 30. Aung MM, Slade K, Freeman LAR, Kos K, Whatmore JL, Shore AC, Gooding KM. Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes. Diabetologia. 2019;62(9):1701-1711.
• 31. Han L, Yu Y, Sun X, Wang B. Exendin-4 directly improves endothelial dysfunction in isolated aortas from obese rats through the cAMP or AMPK-eNOS pathways. Diabetes Res Clin Pract. 2012;97(3):453-460.
• 32. DeNicola M, Du J, Wang Z, Yano N, Zhang L, Wang Y, Qin G, Zhuang S, Zhao TC. Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium. Am J Physiol Endocrinol Metab. 2014;307(8):E630-643.
• 33. Chang G, Zhang P, Ye L, Lu K, Wang Y, Duan Q, Zheng A, Qin S, Zhang D. Protective effects of sitagliptin on myocardial injury and cardiac function in an ischemia/reperfusion rat model. Eur J Pharmacol. 2013;718(1-3):105-113.
• 34. Chinda K, Chattipakorn S, Chattipakorn N. Cardioprotective effects of incretin during ischaemia-reperfusion. Diab Vasc Dis Res. 2012;9:256-269.
• 35. Simanenkova A, Minasian S, Karonova T, Vlasov T, Timkina N, Shpilevaya O, Khalzova A, Shimshilashvili A, Timofeeva V, Samsonov D, Borshchev Y, Galagudza M. Comparative evaluation of metformin and liraglutide cardioprotective effect in rats with impaired glucose tolerance. Sci Rep. 2021;11(1):6700.
• 36. Guan G, Zhang J, Liu S, Huang W, Gong Y, Gu X. Glucagonlike peptide-1 attenuates endoplasmic reticulum stressinduced apoptosis in H9c2 cardiomyocytes during hypoxia/ reoxygenation through the GLP-1R/PI3K/Akt pathways. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(6):715- 722.
• 37. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, Stolarski C, Shen YT, Shannon RP. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004;110(8):955-961.
• 38. Grieve DJ, Cassidy RS, Green BD. Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: Potential therapeutic benefits beyond glycaemic control? Br J Pharmacol. 2009;157(8):1340-1351.
• 39. Chien CT, Jou MJ, Cheng TY, Yang CH, Yu TY, Li PC. Exendin-4-loaded PLGA microspheres relieve cerebral ischemia/reperfusion injury and neurologic deficits through long-lasting bioactivity-mediated phosphorylated Akt/eNOS signaling in rats. J Cereb Blood Flow Metab. 2015;35(11):1790- 1803.
• 40. Li PC, Liu LF, Jou MJ, Wang HK. The GLP-1 receptor agonists exendin-4 and liraglutide alleviate oxidative stress and cognitive and micturition deficits induced by middle cerebral artery occlusion in diabetic mice. BMC Neurosci. 2016;17(1):37.
• 41. Cui X, Liang H, Hao C, Jing X. Liraglutide preconditioning attenuates myocardial ischemia/ reperfusion injury via homer1 activation. Aging. (Albany NY) 2021;13(5):6625-6633.
• 42. Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, Baggio LL, Henkelman RM, Husain M, Drucker DJ. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58(4):975-983.
• 43. Nakatani Y, Kawabe A, Matsumura M, Aso Y, Yasu T, Banba N, Nakamoto T. Effects of GLP-1 receptor agonists on heart rate and the autonomic nervous system using holter electrocardiography and power spectrum analysis of heart rate variability. Diabetes Care. 2016;39(2):e22-23.
• 44. Kaur A, Negi P, Sarna V, Prasad R, Chavan BS, Malhotra A, Kaur G. The appraisement of antioxidant and oxidant status in women undergoing surgical menopause. Indian J Clin Biochem. 2017;32(2):179-185.
• 45. Machi JF, Dias Dda S, Freitas SC, de Moraes OA, da Silva MB, Cruz PL, Mostarda C, Salemi VM, Morris M, De Angelis K, Irigoyen MC. Impact of aging on cardiac function in a female rat model of menopause: Role of autonomic control, inflammation, and oxidative stress. Clin Interv Aging. 2016;11:341-350.
• 46. Hussein AM, Eid EA, Taha M, Elshazli RM, Bedir RF, Lashin LS. Comparative study of the effects of GLP1 analog and SGLT2 inhibitor against diabetic cardiomyopathy in type 2 diabetic rats: Possible underlying mechanisms. Biomedicines. 2020;8(3):43.
• 47. Abdelsameea AA, Abbas NA, Abdel Raouf SM. Liraglutide attenuates partial warm ischemia-reperfusion injury in rat livers. Naunyn Schmiedebergs Arch Pharmacol. 2017;390(3):311-319.
• 48. Chao AM, Tronieri JS, Amaro A, Wadden TA. Semaglutide for the treatment of obesity. Trends Cardiovasc Med. 2021;21:S1050-1738(21)00158-4.