Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-β and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

Department for Experimental Toxicology and Pharmacology National Poison Control Centre Military Medical Academy 11000 Belgrade Serbia

Department of Chemistry Faculty of Science University of Hradec Kralove 500 30 Hradec Kralove Czech Republic

Institute for Medical Research Department for Biomedical Engineering and Biophysics University of Belgrade National Institute of the Republic Serbia 11000 Belgrade Serbia

Institute of Pathology and Forensic Medicine Military Medical Academy 11000 Belgrade Serbia

Laboratory for Experimental Hypertension Institute for Medical Research Department for Cardiovascular Research University of Belgrade National Institute of the Republic Serbia 11000 Belgrade Serbia

Medical Faculty of the Military Medical Academy University of Defence 11000 Belgrade Serbia

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Bauer V., Sotníková R. Nitric oxide--the endothelium-derived relaxing factor and its role in endothelial functions. Gen. Physiol. Biophys. 2010;29:319–340. doi: 10.4149/gpb_2010_04_319. PubMed DOI

Leishman A.W.D. Hypertension—Treated and untreated: A study of 400 cases. Br. Med. J. 1959;1:1361. doi: 10.1136/bmj.1.5134.1361. PubMed DOI PMC

Doggrell S.A., Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc. Res. 1998;39:89–105. doi: 10.1016/S0008-6363(98)00076-5. PubMed DOI

Lerman L.O., Kurtz T.W., Touyz R.M., Ellison D.H., Chade A.R., Crowley S.D., Mattson D.L., Mullins J.J., Osborn J., Eirin A., et al. Animal Models of Hypertension: A Scientific Statement From the American Heart Association. Hypertension. 2019;73:e87–e120. doi: 10.1161/HYP.0000000000000090. PubMed DOI PMC

Grujic-Milanovic J., Miloradovic Z., Jovovic D., Jacevic V., Milosavljevic I., Milanovic S.D., Mihailovic-Stanojevic N. The red wine polyphenol, resveratrol improves hemodynamics, oxidative defence and aortal structure in essential and malignant hypertension. J. Funct. Foods. 2017;34:266–276. doi: 10.1016/j.jff.2017.04.035. DOI

Sventek P., Li J.S., Grove K., Deschepper C.F., Schiffrin E.L. Vascular structure and expression of endothelin-1 gene in L-NAME-treated spontaneously hypertensive rats. Hypertension. 1996;27:49–55. doi: 10.1161/01.HYP.27.1.49. PubMed DOI

Heistad D.D., Wakisaka Y., Miller J., Chu Y., Pena-Silva R. Novel aspects of oxidative stress in cardiovascular diseases. Circ. J. 2009;73:201–207. doi: 10.1253/circj.CJ-08-1082. PubMed DOI PMC

Incalza M.A., D’Oria R., Natalicchio A., Perrini S., Laviola L., Giorgino F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vasc. Pharmacol. 2018;100:1–19. doi: 10.1016/j.vph.2017.05.005. PubMed DOI

Touyz R.M., Rios F.J., Alves-Lopes R., Neves K.B., Camargo L.L., Montezano A.C. Oxidative Stress: A Unifying Paradigm in Hypertension. Can. J. Cardiol. 2020;36:659–670. doi: 10.1016/j.cjca.2020.02.081. PubMed DOI PMC

Greer I.A., Dawes J., Johnston T.A., Calder A.A. Neutrophil activation is confined to the maternal circulation in pregnancy-induced hypertension. Obstet. Gynecol. 1991;78:28–32. doi: 10.1016/0020-7292(92)90078-W. PubMed DOI

Arnhold J. The dual role of myeloperoxidase in immune response. Int. J. Mol. Sci. 2020;21:8057. doi: 10.3390/ijms21218057. PubMed DOI PMC

Zhu M.L., Zhao J.P., Cui N., Gonçalves-Rizzi V.H., Possomato-Vieira J.S., Nascimento R.A., Dias-Junior C.A. Cardiac myeloperoxidase activity is elevated in hypertensive pregnant rats. Curr. Med. Sci. 2017;37:904–909. doi: 10.1007/s11596-017-1825-6. PubMed DOI

Kothari N., Keshari R.S., Bogra J., Kohli M., Abbas H., Malik A., Dikshit M., Barthwal M.K. Increased myeloperoxidase enzyme activity in plasma is an indicator of inflammation and onset of sepsis. J. Crit. Care. 2011;26:435.e1–435.e7. doi: 10.1016/j.jcrc.2010.09.001. PubMed DOI

Tsai S., Hollenbeck S.T., Ryer E.J., Edlin R., Yamanouchi D., Kundi R., Wang C., Liu B., Kent K.C. TGF-beta through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation. Am. J. Physiol. Heart Circ. Physiol. 2009;297:H540–H549. doi: 10.1152/ajpheart.91478.2007. PubMed DOI PMC

Lefer A.M., Ma X.L., Weyrich A.S., Scalia R. Mechanism of the cardioprotective effect of transforming growth factor β1 in feline myocardial ischemia and reperfusion. Proc. Natl. Acad. Sci. USA. 1993;90:1018–1022. doi: 10.1073/pnas.90.3.1018. PubMed DOI PMC

Hockenbery D.M., Zutter M., Hickey W., Nahm M., Korsmeyer S.J. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc. Natl. Acad. Sci. USA. 1991;88:6961–6965. doi: 10.1073/pnas.88.16.6961. PubMed DOI PMC

Oltval Z.N., Milliman C.L., Korsmeyer S.J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death. Cell. 1993;74:609–619. doi: 10.1016/0092-8674(93)90509-O. PubMed DOI

Fraga C.G., Croft K.D., Kennedy D.O., Tomás-Barberán F.A. The effects of polyphenols and other bioactives on human health. Food Funct. 2019;10:514–528. doi: 10.1039/C8FO01997E. PubMed DOI

Droste D.W., Iliescu C., Vaillant M., Gantenbein M., De Bremaeker N., Lieunard C., Velez T., Meyer M., Guth T., Kuemmerle A., et al. Advice on Lifestyle Changes (Diet, Red Wine and Physical Activity) Does Not Affect Internal Carotid and Middle Cerebral Artery Blood Flow Velocity in Patients with Carotid Arteriosclerosis in a Randomized Controlled Trial. Cerebrovasc. Dis. 2014;37:368–375. doi: 10.1159/000362535. PubMed DOI

Opie L.H., Lecour S. The red wine hypothesis: From concepts to protective signalling molecules. Eur. Heart J. 2007;28:1683–1693. doi: 10.1093/eurheartj/ehm149. PubMed DOI

Mihailovic-Stanojevic N., Savikin K., Zivkovic J., Zdunic G., Miloradovic Z., Ivanov M., Karanovic D., Vajic U.J., Jovovic D., Grujic-Milanovic J. Moderate consumption of alcohol-free red wine provide more beneficial effects on systemic haemodynamics, lipid profile and oxidative stress in spontaneously hypertensive rats than red wine. J. Funct. Foods. 2016;26:719–730. doi: 10.1016/j.jff.2016.08.051. DOI

Ronksley P.E., Brien S.E., Turner B.J., Mukamal K.J., Ghali W.A. Association of alcohol consumption with selected cardiovascular disease outcomes: A systematic review and meta-analysis. BMJ. 2011;342:d671. doi: 10.1136/bmj.d671. PubMed DOI PMC

Cheng P.W., Lee H.C., Lu P.J., Chen H.H., Lai C.C., Sun G.C., Yeh T.C., Hsiao M., Lin Y.-T., Liu C.P., et al. Resveratrol Inhibition of Rac1-Derived Reactive Oxygen Species by AMPK Decreases Blood Pressure in a Fructose-Induced Rat Model of Hypertension. Sci. Rep. 2016;6:25342. doi: 10.1038/srep25342. PubMed DOI PMC

Cullberg K.B., Foldager C.B., Lind M., Richelsen B., Pedersen S.B. Inhibitory effects of resveratrol on hypoxia-induced inflammation in 3T3-L1 adipocytes and macrophages. J. Funct. Foods. 2014;7:171–179. doi: 10.1016/j.jff.2014.02.015. DOI

Takashina M., Inoue S., Tomihara K., Tomita K., Hattori K., Zhao Q.L., Suzuki T., Noguchi M., Ohashi W., Hattori Y. Different effect of resveratrol to induction of apoptosis depending on the type of human cancer cells. Int. J. Oncol. 2017;50:787–797. doi: 10.3892/ijo.2017.3859. PubMed DOI

Vázquez-Garza E., Bernal-Ramírez J., Jerjes-Sánchez C., Lozano O., Acuña-Morín E., Vanoye-Tamez M., Ramos-González M.R., Chapoy-Villanueva H., Pérez-Plata L., Sánchez-Trujillo L., et al. Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature. Oxidative Med. Cell. Longev. 2020;2020:1–13. doi: 10.1155/2020/1841527. PubMed DOI PMC

Ungvari Z., Orosz Z., Rivera A., Labinskyy N., Xiangmin Z., Olson S., Podlutsky A., Csiszar A. Resveratrol increases vascular oxidative stress resistance. Am. J. Physiol. Heart Circ. Physiol. 2007;292:2417–2424. doi: 10.1152/ajpheart.01258.2006. PubMed DOI

Toklu H.Z., Şehirli Ö., Erşahin M., Süleymanoǧlu S., Yiǧiner Ö., Emekli-Alturfan E., Yarat A., Yeǧen B.Ç., Şener G. Resveratrol improves cardiovascular function and reduces oxidative organ damage in the renal, cardiovascular and cerebral tissues of two-kidney, one-clip hypertensive rats. J. Pharm. Pharmacol. 2010;62:1784–1793. doi: 10.1111/j.2042-7158.2010.01197.x. PubMed DOI

Senoner T., Dichtl W. Oxidative stress in cardiovascular diseases: Still a therapeutic target? Nutrients. 2019;11:2090. doi: 10.3390/nu11092090. PubMed DOI PMC

Dong Q., Wu Z., Li X., Yan J., Zhao L., Yang C., Lu J., Deng J., Chen M. Resveratrol ameliorates cardiac dysfunction induced by pressure overload in rats via structural protection and modulation of Ca2+ cycling proteins. J. Transl. Med. 2014;12:323. doi: 10.1186/s12967-014-0323-x. PubMed DOI PMC

Harvey A., Montezano A.C., Touyz R.M. Vascular biology of ageing-Implications in hypertension. J. Mol. Cell. Cardiol. 2015;83:112–121. doi: 10.1016/j.yjmcc.2015.04.011. PubMed DOI PMC

Liu Z., Song Y., Zhang X., Liu Z., Zhang W., Mao W., Wang W., Cui W., Zhang X., Jia X., et al. Effects of trans-resveratrol on hypertension-induced cardiac hypertrophy using the partially nephrectomized rat model. Clin. Exp. Pharmacol. Physiol. 2005;32:1049–1054. doi: 10.1111/j.1440-1681.2005.04303.x. PubMed DOI

Sousa T., Afonso J., Carvalho F., Albino-Teixeir A. Lipid Peroxidation and Antioxidants in Arterial Hypertension. Lipid Peroxidation. 2012:345–392. doi: 10.5772/50346. DOI

Tanase D.M., Gosav E.M., Radu S., Ouatu A., Rezus C., Ciocoiu M., Florida Costea C., Floria M. Review Article Arterial Hypertension and Interleukins: Potential Therapeutic Target or Future Diagnostic Marker? Int. J. Hypertens. 2019;2019:3159283. doi: 10.1155/2019/3159283. PubMed DOI PMC

Robb E.L., Winkelmolen L., Visanji N., Brotchie J., Stuart J.A. Dietary resveratrol administration increases MnSOD expression and activity in mouse brain. Biochem. Biophys. Res. Commun. 2008;372:254–259. doi: 10.1016/j.bbrc.2008.05.028. PubMed DOI

Li Y., Cao Z., Zhu H. Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress. Pharmacol. Res. 2006;53:6–15. doi: 10.1016/j.phrs.2005.08.002. PubMed DOI

Dillenburg D.R., Mostarda C., Moraes-Silva I.C., Ferreira D., da Silva GonçalvesBós D., Duarte A.A.M., Irigoyen M.C., Rigatto K. Resveratrol and grape juice differentially ameliorate cardiovascular autonomic modulation in L-NAME-treated rats. Auton. Neurosci. 2013;179:9–13. doi: 10.1016/j.autneu.2013.06.002. PubMed DOI

Ikizler M., Ovali C., Dernek S., Erkasap N., Sevin B., Kaygisiz Z., Kural T. Protective effects of resveratrol in ischemia-reperfusion injury of skeletal muscle: A clinically relevant animal model for lower extremity ischemia. Chin. J. Physiol. 2006;49:204–209. PubMed

Morales A.I., Buitrago J.M., Santiago J.M., Fernandez-Tagarro M., Lopez-Novoa J.M., Perez-Barriocanal F. Protective effect of trans-resveratrol on gentamicin-induced nephrotoxicity. Antioxid. Redox Signal. 2002;4:893–898. doi: 10.1089/152308602762197434. PubMed DOI

Eiserich J.P., Baldus S., Brennan M.L., Ma W., Zhang C., Tousson A., Castro L., Lusis A.J., Nauseef W.M., White C.R., et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science. 2002;296:2391–2394. doi: 10.1126/science.1106830. PubMed DOI

Vanhoutte P.M., Shimokawa H., Tang E.H.C., Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol. 2009;196:193–222. doi: 10.1111/j.1748-1716.2009.01964.x. PubMed DOI

Mata-Greenwood E., Grobe A., Kumar S., Noskina Y., Black S.M. Cyclic stretch increases VEGF expression in pulmonary arterial smooth muscle cells via TGF-beta1 and reactive oxygen species: A requirement for NAD(P)H oxidase. Am. J. Physiol. Lung Cell. Mol. Physiol. 2005;289:L288–L289. doi: 10.1152/ajplung.00417.2004. PubMed DOI

Popovic N., Bridenbaugh E.A., Neiger J.D., Hu J.-J., Vannucci M., Mo Q., Trzeciakowski J., Miller M.W., Fossum T.W., Humphrey J.D., et al. Transforming growth factor-beta signaling in hypertensive remodeling of porcine aorta. Am. J. Physiol. Heart Circ. Physiol. 2009;297:H2044–H2053. doi: 10.1152/ajpheart.01015.2008. PubMed DOI PMC

Liu R.M., Desai L.P. Reciprocal regulation of TGF-β and reactive oxygen species: A perverse cycle for fibrosis. Redox Biol. 2015;6:565–577. doi: 10.1016/j.redox.2015.09.009. PubMed DOI PMC

Misao J., Hayakawa Y., Ohno M., Kato S., Fujiwara T., Fujiwara H. Expression of bcl-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction. Circulation. 1996;94:1506–1512. doi: 10.1161/01.CIR.94.7.1506. PubMed DOI

Krajewski S., Krajewska M., Shabaik A., Miyashita T., Wang H.G., Reed J.C. Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am. J. Pathol. 1994;145:1323–1336. PubMed PMC

Miloradović Z., Jerkić M., Jovović D., Mihailović-Stanojević N., Grujić Milanović J., Stošcic G., Marković-Lipkovski J. Bosentan and losartan ameliorate acute renal failure associated with mild but not strong NO blockade. Nephrol. Dial. Transplant. 2007;22:2476–2484. doi: 10.1093/ndt/gfm213. PubMed DOI

Ohkawa H., Ohishi N., Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 1979;95:351–358. doi: 10.1016/0003-2697(79)90738-3. PubMed DOI

Selmeci L., Seres L., Antal M., Lukács J., Regöly-Mérei A., Acsády G. Advanced oxidation protein products (AOPP) for monitoring oxidative stress in critically ill patients: A simple, fast and inexpensive automated technique. Clin. Chem. Lab. Med. 2005;43:294–297. doi: 10.1515/CCLM.2005.050. PubMed DOI

Ellman G.L. Tissue sulfhydryl groups. Arch. Biochem. Biophys. 1959;82:70–77. doi: 10.1016/0003-9861(59)90090-6. PubMed DOI

Pick E., Keisari Y. A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J. Immunol. Methods. 1980;38:161–170. doi: 10.1016/0022-1759(80)90340-3. PubMed DOI

Alamdari D.H., Paletas K., Pegiou T., Sarigianni M., Befani C., Koliakos G. A novel assay for the evaluation of the prooxidant-antioxidant balance, before and after antioxidant vitamin administration in type II diabetes patients. Clin. Biochem. 2007;40:248–254. doi: 10.1016/j.clinbiochem.2006.10.017. PubMed DOI

Paglia D.E., Valentine W.N. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med. 1967;70:158–169. PubMed

McCord J.M., Fridovich I. The reduction of cytochrome c by milk xanthine oxidase. J. Biol. Chem. 1968;243:5753–5760. doi: 10.1016/S0021-9258(18)91929-0. PubMed DOI

Glatzle D., Vuilleumier J.P., Weber F., Decker K. Glutathione reductase test with whole blood, a convenient procedure for the assessment of the riboflavin status in humans. Experientia. 1974;30:665–667. doi: 10.1007/BF01921531. PubMed DOI

Beutler E. Catalasa. In: Beutler E., editor. Red Cell Metabolism, a Manual of Biochemical Methods. Grune and Stratton; New York, NY, USA: 1982.

Jaćević V., Wu Q., Nepovimova E., Kuča K. Efficacy of methylprednisolone on T-2 toxin-induced cardiotoxicity in vivo: A pathohistological study. Environ. Toxicol. Pharmacol. 2019;71:103221. doi: 10.1016/j.etap.2019.103221. PubMed DOI

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