Alleviation of oxidized lipid-induced oxidative stress and hypertension by estrogen and selected antihyperlipidemic drugs in post-menopausal Wistar rats
Lipid peroxidation is implicated in the development of hypertension and coronary artery disease, and its deleterious impact is exacerbated by estrogen (ETD) depletion in post-menopausal women. We hypothesize that treatment with ETD and antihyperlipidemic drugs, either alone or in combination, can alleviate the development of cardiovascular disease. In this study, female Wistar rats were divided into 10 groups (n = 6): Group 1 (control) underwent a Sham operation and was fed standard rat chow, whereas the other nine groups were ovariectomized (OVX) and received a diet containing either thermoxidized palm oil (TPO) or thermoxidized soya oil (TSO) for 12 weeks. ETD at 0.2 mg/kg/day, atorvastatin (ATV) at 10 mg/kg/day, and a combination of ezetimibe (EZE) and ATV (EZE at 3 mg/kg/day + ATV at 10 mg/kg/day) were administered for 12 weeks in both TSO and TPO diet groups. Blood pressure and electrocardiogram (ECG) parameters were assessed, along with serum lipid profile, atherogenic indices, and markers of oxidative stress. Both TPO and TSO diets significantly altered blood pressure and ECG parameters in OVX rats. Treatment with ATV, EZE+ATV, and ETD significantly reduced blood pressure parameters compared to the OVX+TPO group. Antihyperlipidemic drugs significantly decreased heart rate, QT interval, QRS duration, and QT corrected (QTc), whereas ETD similarly shortened the QRS and QTc duration. ATV and ETD also reduced total cholesterol, triglycerides, and very low-density lipoprotein levels, while boosting high-density lipoprotein concentrations compared to untreated OVX+TSO rats. This study demonstrates that thermoxidized oil has a deleterious effect on OVX rats by altering blood pressure, ECG parameters, and atherogenic indices. Treatment with antihyperlipidemic drugs and ETD normalized blood pressure and ECG parameters, reversed hyperlipidemia, and restored antioxidant system balance.
- United States Department of Agriculture. Washington: Global Oilseed Demand Growth Forecast to Outpace Production (Again). Oilseeds: World Markets and Trade; 2018. Available from: https://www.fas.usda.gov/data/oilseedsworldmarkets-and-trade [Last accessed on 2021 Apr 23].
- Unhapipatpong C, Shantavasinkul PC, Kasemsup V, et al. Tropical oil consumption and cardiovascular disease: An umbrella review of systematic reviews and meta analyses. Nutrients. 2021;13(5):1549. doi: 10.3390/nu13051549
- Sacks FM, Lichtenstein AH, Wu J, et al. Dietary fats and cardiovascular disease: A presidential advisory from the American heart association. Circulation. 2017;136(3):e1-e23. doi: 10.1161/CIR.0000000000000510
- Falade AO, Oboh G. Thermal oxidation induces lipid peroxidation and changes in the physicochemical properties and β-carotene content of Arachis oil. Int J Food Sci. 2015;2015:806524. doi: 10.1155/2015/806524
- Awney HA. The effects of Bifidobacteria on the lipid profile and oxidative stress biomarkers of male rats fed thermally oxidized soybean oil. Biomarkers. 2011;16(5):445-452. doi: 10.3109/1354750X.2011.590228.
- Hur SJ, Min B, Nam KC, Lee EJ, Ahn DU. Effect of dietary cholesterol and cholesterol oxides on blood cholesterol, lipids, and the development of atherosclerosis in rabbits. Int J Mol Sci. 2013;14(6):12593-12606. doi: 10.3390/ijms140612593
- Ng CY, Leong XF, Masbah N, Adam SK, Kamisah Y, Jaarin K. Reprint of “heated vegetable oils and cardiovascular disease risk factors”. Vasc Pharmacol. 2014;62(1):38-46. doi: 10.1016/j.vph.2014.05.003
- Anand SS, Islam S, Rosengren A, et al. Risk factors for myocardial infarction in women and men: Insights from the interheart study. Eur Heart J. 2008;29(7):932-940. doi: 10.1093/eurheartj/ehn018
- Rosano GM, Vitale C, Marazzi G, Volterrani M. Menopause and cardiovascular disease: The evidence. Climacteric. 2007;10(Suppl 1):19-24. doi: 10.1080/13697130601114917
- El Khoudary SR, Aggarwal B, Beckie TM, et al. Menopause transition and cardiovascular disease risk: Implications for timing of early prevention: A scientific statement from the American heart association. Circulation. 2020;142(25):e506-e532. doi: 10.1161/CIR.0000000000000912
- Ashraf MS, Vongpatanasin W. Estrogen and hypertension. Curr Hypertens Rep. 2006;8(5):368-376. doi: 10.1007/s11906-006-0080-1
- Maas AHEM, Franke HR. Women’s health in menopause with a focus on hypertension. Neth Heart J. 2009;17(2):68-72. doi: 10.1007/BF03086220
- Sabbatini AR, Kararigas G. Estrogen-related mechanisms in sex differences of hypertension and target organ damage. Biol Sex Differ. 2020;11:1-17. doi: 10.1186/s13293-020-00306-7
- Patki G, Allam FH, Atrooz F, et al. Grape powder intake prevents ovariectomy-induced anxiety-like behavior, memory Impairment and high blood pressure in female Wistar rats. PLoS One. 2013;8(9):e74522. doi: 10.1371/journal.pone.0074522
- Ko SH, Kim HS. Menopause-associated lipid metabolic disorders and foods beneficial for postmenopausal women. Nutrients. 2020;12(1):202. doi: 10.3390/nu12010202
- Owu DU, Osim EE, Ebong PE. Serum liver enzymes profile of Wistar rats following chronic consumption of fresh or oxidized palm oil diets. Acta Trop. 1998;69(1):65-73. doi: 10.1016/s0001-706x(97)00115-0
- Chong C, Othman F, Hussan F. Vascular protective effects of Morinda citrifolia leaf extract on postmenopausal rats fed with thermoxidized palm oil diet: Evidence at microscopic level. Int J Vasc Med. 2018;2018:6317434. doi: 10.1155/2018/6317434
- Singh SV, Shrivastava A, Chaturvedi U, et al. A mechanism-based pharmacological evaluation of efficacy of Flacourtia indica in management of dyslipidemia and oxidative stress in hyperlipidemic rats. J Basic Clin Physiol Pharmacol. 2016;27(2):121-129. doi: 10.1515/jbcpp-2015-0017
- Harnafi H, Caid HS, El Houda Bouanani N, Aziz M, Amrani S. Hypolipidaemic activity of aqueous Ocimum basilicum extract in acute hyperlipidaemia induced by triton WR-1339 in rats and its antioxidant property. Food Chem. 2008;108(1):205-212. doi: 10.1002/ptr.1961
- Joerin L, Kauschka M, Bonnländer B, Pischel I, Benedek B, Butterweck V. Ficus carica leaf extract modulates the lipid profile of rats fed with a high‐fat diet through an increase of HDL‐C. Phytother Res. 2014;28(2):261-267. doi: 10.1002/ptr.4994
- Nagababu E, Rifkind JM, Boindala S, Nakka L. Assessment of antioxidant activity of eugenol in vitro and in vivo. In: Free Radicals and Antioxidant Protocols. United States: Humana Press; 2010. p. 165-180. doi: 10.1007/978-1-60327-029-8_10
- Jollow DJ, Mitchell JR, Zampaglione NA, Gillette JR. Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology. 1974;11(3):151-169. doi: 10.1159/000136485
- Goth L. A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta. 1991;196(2-3):143-151. doi: 10.1016/0009-8981(91)90067-m
- Misra, HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247:3170-3175.
- El Khoudary, SR, Thurston RC. Cardiovascular implications of the menopause transition: endogenous sex hormones and vasomotor symptoms. Obstetr Gynecol Clin North Am. 2018;45(4):641-661. doi: 10.1016/j.ogc.2018.07.006
- Xian TK, Omar, NA, Ying LW, et al. Reheated palm oil consumption and risk of atherosclerosis: Evidence at ultrastructural level. Evid Based Complement Alternat Med. 2012;2012:828170. doi: 10.1155/2012/828170
- Che Idris CA, Sundram K, Abdull Razis AF. Correction: Che Idris et al. Effect of consumption heated oils with or without dietary cholesterol on the development of atherosclerosis. Nutrients 2018;10:1527. Nutrients. 2018;10(12):1839. doi: 10.3390/nu10121839
- Brandsch C, Eder K. Effects of peroxidation products in thermoxidised dietary oil in female rats during rearing, pregnancy and lactation on their reproductive performance and the antioxidative status of their offspring. Br J Nutr. 2004;92(2):267-275. doi: 10.1079/BJN20041195
- Choe E, Min DB. Chemistry of deep-fat frying oils. J Food Sci. 2007;72(5):R77-R86. doi: 10.1111/j.1750-3841.2007.00352.x
- Leong XF, Mustafa MR, Das S, Jaarin K. Association of elevated blood pressure and impaired vasorelaxation in experimental Sprague-Dawley rats fed with heated vegetable oil. Lipids Health Dis. 2010;9:66. doi: 10.1186/1476-511X-9-66
- Jaarin K, Mustafa MR, Leong XF. The effects of heated vegetable oils on blood pressure in rats. Clinics (Sao Paulo). 2011;66(12):2125-2132. doi: 10.1590/s1807-59322011001200020
- Ruixing Y, Jinzhen W, Weixiong L, Yuming C, Dezhai Y, Shangling, P. The environmental and genetic evidence for the association of hyperlipidemia and hypertension. J Hypertens. 2009;27(2):251-258. doi: 10.1097/hjh.0b013e32831bc74d
- Cífková R. Antiplatelet and lipid-lowering drugs in hypertension. Eur Cardiol. 2009;9(1):16-20. doi: 10.15420/ecr.2014.9.1.16
- Kesmati M, Torabi M, Pourreza N, Tayebkhah M, Asadi F. Effects of anxiolytic doses of ZnO nanoparticle on ECG parameters in restraint and non-restraint ovariectomized female rats. Nanomed Res J. 2019;4(4):253-260. doi: 10.22034/nmrj.2019.04.008
- Cubeddu LX. QT prolongation and fatal arrhythmias: A review of clinical implications and effects of drugs. Am J Ther. 2003;10(6):452-457. doi: 10.1097/00045391-200311000-00013
- White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis. 2007;7(8):549-558. doi: 10.1016/s1473-3099(07)70187-1
- Brites F, Martin M, Guillas I, Kontush A. Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit. BBA Clin. 2017;8:66-77. doi: 10.1016/j.bbacli.2017.07.002
- Adiels M, Olofsson SO, Taskinen MR, Borén J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(7):1225-1236. doi: 10.1161/atvbaha.107.160192
- Nayak IN, Chinta R, Jetti R. Anti-atherosclerotic potential of aqueous extract of Cinnamomum zeylanicum bark against glucocorticoid induced atherosclerosis in Wistar rats. J Clin Diagn Res. 2017;11(5):FC19. doi: 10.7860/jcdr/2017/23910.9864
- Marvar PJ, Lob H, Vinh A, Zarreen F, Harrison DG. The central nervous system and inflammation in hypertension. Curr Opinion Pharmacol. 2011;11(2):156. doi: 10.1016/j.coph.2010.12.001
- Drummond GR, Vinh A, Guzik TJ, Sobey CG. Immune mechanisms of hypertension. Nat Rev Immunol. 2019;19(8):517-532. doi: 10.1038/s41577-019-0160-5
- Förstermann U, Xia N, Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res. 2017;120(4):713-735. doi: 10.1161/circresaha.116.309326
- Vinh A, Drummond GR, Sobey CG. Immunity and hypertension: New targets to lighten the pressure. Br J Pharmacol. 2019;176(12):1813-1817. doi: 10.1111/bph.14659
- Elahi MM, Kong YX, Matata BM. Oxidative stress as a mediator of cardiovascular disease. Oxid Med Cell Longev. 2009;2(5):259-269. doi: 10.4161/oxim.2.5.9441
- Agita A, Alsagaff MT. Inflammation, immunity, and hypertension. Acta Med Indones. 2017;49(2):158-165.
- Florian M, Freiman A, Magder S. Treatment with 17-β-estradiol reduces superoxide production in aorta of ovariectomized rats. Steroids. 2004;69(13-14):779-787. doi: 10.1016/j.steroids.2004.09.008
- Zhang L, Fujii S, Kosaka H. Effect of oestrogen on reactive oxygen species production in the aortas of ovariectomized Dahl salt-sensitive rats. J Hypertension. 2007;25(2):407-414. doi: 10.1097/hjh.0b013e328010beee
- Jeanes HL, Tabor C, Black D, Ederveen A, Gray GA. Oestrogen-mediated cardioprotection following ischaemia and reperfusion is mimicked by an oestrogen receptor (ER) alpha agonist and unaffected by an ER beta antagonist. J Endocrinol. 2008;197(3):493-501. doi: 10.1677/joe-08-0071
- Xiang D, Liu Y, Zhou S, Zhou E, Wang Y. Protective effects of estrogen on cardiovascular disease mediated by oxidative stress. Oxid Med Cell Longev. 2021;2021:5523516. doi: 10.1155/2021/5523516
- Dhaunsi GS, Yousif MH, Akhtar S, Chappell MC, Diz DI, Benter IF. Angiotensin-(1-7) prevents diabetes-induced attenuation in PPAR-gamma and catalase activities. Eur J Pharmacol. 2010;638(1-3):108-114. doi: 10.1016/j.ejphar.2010.04.030
- Adam SK, Das S, Soelaiman IN, Umar NA, Jaarin K. Consumption of repeatedly heated soy oil increases the serum parameters related to atherosclerosis in ovariectomized rats. Tohoku J Exp Med. 2008;215(3):219-226. doi: 10.1620/tjem.215.219
- Chong CL, Hussan F, Othman F. Hepatoprotective effects of morinda citrifolia leaf extract on ovariectomized rats fed with thermoxidized palm oil diet: Evidence at histological and ultrastructural level. Oxid Med Cell Longev. 2019;2019:9714302. doi: 10.1155/2019/9714302