PROTECTIVE EFFECT OF NQO-1 MODULATOR QUERCETIN IN HYPERTENSIVE RATS
Abstract
Despite abundant anti-hypertensive therapies, there always remains an opportunity (perhaps need) to identify novel targets. One such emerging target is NAD(P)H:quinone oxidoreductase 1 (NQO-1), which acts downstream in Nrf2 cascade. This study was planned to investigate the effect of Nrf2 activator quercetin on NQO-1 modulation in hypertensive wistar albino rats. The hypertension was induced by DOCA (25 mg/kg s.c. twice weekly) and 1% NaCl in drinking water. The animals were randomized into six groups receiving either vehicle (control), DOCA- 1% NaCl salt (model) or treatments (Telmisartan (10 mg/kg) and quercetin (10, 25, 50 mg/kg) for 5 weeks. Various haemodynamic parameters, left ventricular functions, biological markers, lipid and protein peroxidative marker, antioxidant enzymes activity as well as histology (heart and kidney) were carried out. The expression of mRNA of NQO-1 gene in heart homogenate was estimated. Treatment with quercetin significantly prevented the rise in blood pressure, organ weight, improved left ventricular function, cardiac markers profile, kidney markers, restored antioxidant enzymes along with decrease in lipid and protein peroxidation. The normal architecture of heart and kidney were preserved in histopathological analysis by quercetin treatment. The upregulation of NQO-1 gene in heart by quercetin resulted in normal blood pressure. Altogether, quercetin prevented hypertension, improved cardiac function by augmenting the innate cell defense system in DOCA-salt rats. Such promising effects are attributed to novel cellular level target, NQO-1, which have multiple effects like regularisation of oxidative stress, eNOS activation and inhibition of ACE shedding.
Keywords:
Quercetin, DOCA-salt, Hypertension, NQO-1, Oxidative stressDOI
https://doi.org/10.25004/IJPSDR.2022.140606References
World Health Organization: Cardiovascular diseases (CVDs) 2021 [updated 11 June 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).
World Health Organisation: Hypertension 2021 [Available from: https://www.who.int/health-topics/hypertension#tab=tab_1.
Ramakrishnan S, Zachariah G, Gupta K, Rao JS, Mohanan P, Venugopal K, et al. Prevalence of hypertension among Indian adults: results from the great India blood pressure survey: Indian Heart Journal. 2019;71(4):309-313.
Tripathi K. Hypertension. Essentials of Medical Pharmacology. Eighth ed: Jaypee Brothers Medical Publishers; 2018. pp 604-620.
Al Disi SS, Anwar MA, Eid AH. Anti-hypertensive herbs and their mechanisms of action: part I: Frontiers in Pharmacology. 2016;6:323-347.
World Health Organization: WHO global report on traditional and complementary medicine 2019: World Health Organization; 2019.
Atia A, Abdullah A. NQO1 enzyme and its role in cellular protection; an insight: Iberoamerican Journal of Medicine. 2020;2(4):306-313.
Liang L, Gao C, Luo M, Wang W, Zhao C, Zu Y, et al. Dihydroquercetin (DHQ) induced HO-1 and NQO1 expression against oxidative stress through the Nrf2-dependent antioxidant pathway: Journal of Agricultural Food Chemistry. 2013;61(11):2755-2761.
Tanigawa S, Fujii M, Hou D-X. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin: Free Radical Biology Medicine. 2007;42(11):1690-1703.
Schadich E, Hlaváč J, Volná T, Varanasi L, Hajdúch M, Džubák P. Effects of ginger phenylpropanoids and quercetin on Nrf2-ARE pathway in human BJ fibroblasts and HaCaT keratinocytes: BioMed research international. 2016;2016:1-6.
Valerio Jr L, Kepa J, Pickwell G, Quattrochi L. Induction of human NAD (P) H: quinone oxidoreductase (NQO1) gene expression by the flavonol quercetin: Toxicology letters. 2001;119(1):49-57.
Alrawaiq NS, Atia A, Abdullah A. The effect of administration of an equal dose of different classes of dietary chemicals on NQO1 expressional level in mice liver: Pharmacophore 2017;8(5):1-9.
Sharma B, Singh N. Experimental hypertension induced vascular dementia: pharmacological, biochemical and behavioral recuperation by angiotensin receptor blocker and acetylcholinesterase inhibitor: Pharmacology Biochemistry Behavior. 2012;102(1):101-108.
Sawant SH, Bodhankar SL. Flax lignan concentrate reverses alterations in blood pressure, left ventricular functions, lipid profile and antioxidant status in DOCA-salt induced renal hypertension in rats: Renal Failure. 2016;38(3):411-423.
Gandhi T, Singh A, Patel A, Karia P, Shah H. Sodium current inhibitor ranolazine ameliorates experimentally induced diabetic cardio¬myopathy: Journal f Research in Pharmacy. 2020;24(6):842-854.
Iyer A, Chan V, Brown L. The DOCA-salt hypertensive rat as a model of cardiovascular oxidative and inflammatory stress: Current Cardiology Reviews. 2010;6(4):291-297.
Duarte J, Pérez‐Palencia R, Vargas F, Angeles Ocete M, Pérez‐Vizcaino F, Zarzuelo A, et al. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats: British Journal of Pharmacology. 2001;133(1):117-124.
Duarte J, Pérez-Vizcaíno F, Zarzuelo A, Jiménez J, Tamargo J. Vasodilator effects of quercetin in isolated rat vascular smooth muscle: European Journal of Pharmacology. 1993;239(1-3):1-7.
Duarte J, Utrilla P, Jimenez J, Tamargo J, Zarzuelo A. Vasodilatory effects of flavonoids in rat aortic smooth muscle. Structure-activity relationships: General Pharmacology. 1993;24(4):857-862.
Larson AJ, Symons JD, Jalili T. Therapeutic potential of quercetin to decrease blood pressure: review of efficacy and mechanisms: Advances in Nutrition. 2012;3(1):39-46.
Obiefuna I, Young R. Concurrent administration of aqueous Azadirachta indica (neem) leaf extract with DOCA‐salt prevents the development of hypertension and accompanying electrocardiogram changes in the rat: Phytotherapy Research: An International Journal Devoted to Pharmacological Toxicological Evaluation of Natural Product Derivatives. 2005;19(9):792-795.
Baldo MP, Teixeira AKG, Rodr igues SL, Mi l l JG. Acute arrhythmogenesis after myocardial infarction in normotensive rats: influence of high salt intake: Food chemical toxicology. 2012;50(3-4):473-477.
Basting T, Lazartigues E. DOCA-salt hypertension: an update: Current Hypertension Reports. 2017;19(4):1-8.
Chan V, Hoey A, Brown L. Improved cardiovascular function with aminoguanidine in DOCA‐salt hypertensive rats: British Journal of Pharmacology. 2006;148(7):902-908.
Kumar A, Sharma P, Kumar P, Kumar A. Study of panel of diagnostic cardiac markers for acute myocardial infarction: Asian Journal of Pharmaceutical and Clinical Research. 2019;12(3):181-184.
Leiba A, Vald A, Peleg E, Shamiss A, Grossman E. Does dietary recall adequately assess sodium, potassium, and calcium intake in hypertensive patients?: Nutrition. 2005;21(4):462-466.
Schenk J, McNeill JHJ. The pathogenesis of DOCA-salt hypertension: Journal of Pharmacological Toxicological Methods. 1992;27(3):161- 170.
Kim Y-H, Hwang JH, Kim K-S, Noh J-R, Gang G-T, Kim S-W, et al. NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats: Cardiovascular Research. 2013;99(4):743-750.
Kim Y-H, Hwang JH, Noh J-R, Gang G-T, Kim DH, Son H-Y, et al. Activation of NAD (P) H: quinone oxidoreductase ameliorates spontaneous hypertension in an animal model via modulation of eNOS activity: Cardiovascular research. 2011;91(3):519-527.
Fenning A, Harrison G, Rose’meyer R, Hoey A, Brown L. L-Arginine attenuates cardiovascular impairment in DOCA-salt hypertensive rats: American Journal of Physiology-Heart Circulatory Physiology. 2005;58(4 ):H1408-H1416.
Lindoso RS, Lopes JA, Binato R, Abdelhay E, Takiya CM, de Miranda KR, et al. Adipose mesenchymal cells-derived EVs alleviate DOCA-salt-induced hypertension by promoting cardio-renal protection: Molecular Therapy-Methods Clinical Development. 2020;16:63-77.
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