Abstract
Aim:
Sesamin is one of the major lignans in sesame seeds with antihyperlipidemic, antioxidative and antihypertensive activities. The aim of this study was to examine the effects of sesamin on arterial function in spontaneously hypertensive rats (SHRs).
Methods:
SHRs were orally administered sesamin (40, 80 and 160 mg·kg−1·d−1) for 16 weeks. After the rats were killed, thoracic aortas were dissected out. The vasorelaxation responses of aortic rings to ACh and nitroprusside were measured. The expression of eNOS and NADPH oxidase subunits p47phox and p22phox in aortas were detected using Western blotting and immunohistochemistry. Aortic nitrotyrosine was measured with ELISA. The total antioxidant capacity (T-AOC) and MDA levels in aortas were also determined.
Results:
The aortic rings of SHRs showed significantly smaller ACh-induced and nitroprusside-induced relaxation than those of control rats. Treatment of SHRs with sesamin increased both the endothelium-dependent and endothelium-independent relaxation of aortic rings in a dose-dependent manner. In aortas of SHRs, the level of T-AOC and the expression of nitrotyrosine, p22phox and p47phox proteins were markedly increased, while the level of MDA and the expression of eNOS protein were significantly decreased. Treatment of SHRs with sesamin dose-dependently reversed these biochemical and molecular abnormalities in aortas.
Conclusion:
Long-term treatment with sesamin improves arterial function in SHR through the upregulation of eNOS expression and downregulation of p22phox and p47phox expression.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Touyz RM, Schiffrin EL . Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004; 122: 339–52.
Feletou M, Vanhoutte PM . Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 2006; 291: H985–H1002.
Rizzoni D, Castellano M, Porteri E, Bettoni G, Muiesan ML, Agabiti-Rosei E . Vascular structural and functional alterations before and after the development of hypertension in SHR. Am J Hypertens 1994; 7: 193–200.
Suzuki H, Swei A, Zweifach BW, Schmid-Schönbein GW . In vivo evidence for microvascular oxidative stress in spontaneously hypertensive rats. Hydroethidine microfluorography. Hypertension 1995; 25: 1083–9.
El-Remessy AB, Tawfik HE, Matragoon S, Pillai B, Caldwell RB, Caldwell RW . Peroxynitrite mediates diabetes-induced endothelial dysfunction: Possible role of Rho kinase activation. Exp Diabetes Res 2010; 2010: 247861.
Sánchez M, Galisteo M, Vera R, Villar IC, Zarzuelo A, Tamargo J, et al. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J Hypertens 2006; 24: 75–84.
Ülker S, McKeown PP, Bayraktutan U . Vitamins reverse endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities. Hypertension 2003; 41: 534–9.
Zalba G, Beaumont FJ, San José G, Fortuño A, Fortuño MA, Etayo JC, et al. Vascular NADH/NADPH oxidase is involved in enhanced superoxide production in spontaneously hypertensive rats. Hypertension 2000; 35: 1055–61.
Touyz RM . Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension 2004; 44: 248–52.
Förstermann U, Münzel T . Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 2006; 113: 1708–14.
Förstermann U, Sessa WC . Nitric oxide synthases: regulation and function. Eur Heart J 2012; 33: 829–37
Förstermann U . Nitric oxide and oxidative stress in vascular disease. Pflugers Arch 2010; 459: 923–39.
Alderton WK, Cooper CE, Knowles RG . Nitric oxide synthases: structure, function and inhibition. Biochem J 2001; 357: 593–615.
McIntyre M, Bohr DF, Dominiczak AF . Endothelial function in hypertension: the role of superoxide anion. Hypertension 1999; 34: 539–45.
Hirose N, Inoue T, Nishihara K, Sugano M, Akimoto K, Shimizu S, et al. Inhibition of cholesterol absorption and synthesis in rats by sesamin. J Lipid Res 1991; 32: 629–38.
Ide T, Hong DD, Ranasinghe P, Takahashi Y, Kushiro M, Sugano M . Interaction of dietary fat types and sesamin on hepatic fatty acid oxidation in rats. Biochim Biophys Acta 2004; 1682: 80–91.
Kita S, Matsumura Y, Morimoto S, Akimoto K, Furuya M, Oka N, et al. Antihypertensive effect of sesamin. II. Protection against two-kidney, one-clip renal hypertension and cardiovascular hypertrophy. Biol Pharm Bull 1995; 18: 1283–5.
Kong X, Yang JR, Guo LQ, Xiong Y, Wu XQ, Huang K, et al. Sesamin improves endothelial dysfunction in renovascular hypertensive rats fed with a high-fat, high-sucrose diet. Eur J Pharmacol 2009; 620: 84–9.
Matsumura Y, Kita S, Morimoto S, Akimoto K, Furuya M, Oka N, et al. Antihypertensive effect of sesamin. I. Protection against deoxycorticosterone acetate-salt-induced hypertension and cardiovascular hypertrophy. Biol Pharm Bull 1995; 18: 1016–9.
Matsumura Y, Kita S, Tanida Y, Taguchi Y, Morimoto S, Akimoto K, et al. Antihypertensive effect of sesamin. III. Protection against development and maintenance of hypertension in stroke-prone spontaneously hypertensive rats. Biol Pharm Bull 1998; 21: 469–73.
Miyawaki T, Aono H, Toyoda-Ono Y, Maeda H, Kiso Y, Moriyama K . Antihypertensive effects of sesamin in humans. J Nutr Sci Vitaminol (Tokyo) 2009; 55: 87–91.
Nakano D, Itoh C, Ishii F, Kawanishi H, Takaoka M, Kiso Y, et al. Effects of sesamin on aortic oxidative stress and endothelial dysfunction in deoxycorticosterone acetate-salt hypertensive rats. Biol Pharm Bull 2003; 26: 1701–5.
Ogawa H, Sasagawa S, Murakami T, Yoshizumi H, Shimizu S, Yamada H . Effects of sesamin on serum lipoprotein metabolism in normocholesterolemic and hypercholesterolemic stroke-prone SHR. Ann N Y Acad Sci 1993; 676: 338–9.
Nakano D, Kwak CJ, Fujii K, Ikemura K, Satake A, Ohkita M, et al. Sesamin metabolites induce an endothelial nitric oxide-dependent vasorelaxation through their antioxidative property-independent mechanisms: possible involvement of the metabolites in the antihypertensive effect of sesamin. J Pharmacol Exp Ther 2006; 318: 328–35.
Nakano D, Kurumazuka D, Nagai Y, Nishiyama A, Kiso Y, Matsumura Y . Dietary sesamin suppresses aortic NADPH oxidase in DOCA salt hypertensive rats. Clin Exp Pharmacol Physiol 2008; 35: 324–6.
Wu XQ, Kong X, Zhou Y, Huang K, Yang JR, Li XL . Sesamin exerts renoprotective effects by enhancing NO bioactivity in renovascular hypertensive rats fed with high-fat-sucrose diet. Eur J Pharmacol 2012; 683: 231–7.
Rodriguez-Martinez MA, Ruiz-Torres A . Homeostasis between lipid peroxidation and antioxidant enzyme activities in healthy human aging. Mech Ageing Dev 1992; 66: 213–322.
Manso MA, Miguel M, Even J, Hernandez R, Aleixandre MA, López-Fandiño R . Effect of the long-term intake of an egg white hydrolysate on the oxidative status and blood lipid profile of spontaneously hypertensive rats. Food Chemistry 2008; 109: 361–7.
Benzie IF, Strain JJ . The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Anal Biochem 1996; 239: 70–6.
ter Steege JC, Koster-Kamphuis L, van Straaten EA, Forget PP, Buurman WA . Nitrotyrosine in plasma of celiac disease patients as detected by a new sandwich ELISA. Free Radic Biol Med 1998; 25: 953–63.
Patterson C, Ruef J, Madamanchi NR, Barry-Lane P, Hu Z, Horaist C, et al. Stimulation of a vascular smooth muscle cell NAD(P)H oxidase by thrombin. Evidence that p47 (phox) may participate in forming this oxidase in vitro and in vivo. J Biol Chem 1999; 274: 19814–22.
Potenza MA, Gagliardi S, De Benedictis L, Zigrino A, Tiravanti E, Colantuono G, et al. Treatment of spontaneously hypertensive rats with rosiglitazone ameliorates cardiovascular pathophysiology via antioxidant mechanisms in the vasculature. Am J Physiol Endocrinol Metab 2009; 297: E685–94.
Hägg U, Andersson I, Naylor AS, Grönros J, Jonsdottir IH, Bergström G, et al. Voluntary physical exercise-induced vascular effects in spontaneously hypertensive rats. Clin Sci (Lond) 2004; 107: 571–81.
Gao L, Wang F, Wang B, Gong B, Zhang J, Zhang X, et al. Cilostazol protects diabetic rats from vascular inflammation via nuclear factor-kappa B-dependent down-regulation of vascular cell adhesion molecule-1 expression. J Pharmacol Exp Ther 2006; 318: 53–8.
Gu K, Zhao JD, Ren ZG, Ma NY, Lai ST, Wang J, et al. A natural process of cirrhosis resolution and deceleration of liver regeneration after thioacetamide withdrawal in a rat model. Mol Biol Rep 2011; 38: 1687–96.
López-Sepúlveda R, Jiménez R, Romero M, Zarzuelo MJ, Sánchez M, Gómez-Guzmán M, et al. Wine polyphenols improve endothelial function in large vessels of female spontaneously hypertensive rats. Hypertension 2008; 51: 1088–95.
Roberts CK, Vaziri ND, Wang XQ, Barnard RJ . Enhanced NO inactivation and hypertension induced by a high-fat, refined-carbohydrate diet. Hypertension 2000; 36: 423–9.
Xu C, Lee S, Singh TM, Sho E, Li X, Sho M, et al. Molecular mechanisms of aortic wall remodeling in response to hypertension. J Vasc Surg 2001; 33: 570–8.
Lüscher TF, Vanhoutte PM . Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 1986; 8: 344–8.
Yang D, Félétou M, Boulanger CM, Wu HF, Levens N, Zhang JN, et al. Oxygen-derived free radicals mediate endothelium-dependent contractions to acetylcholine in aortas from spontaneously hypertensive rats. Br J Pharmacol 2002; 136: 104–10.
Li H, Förstermann U . Nitric oxide in the pathogenesis of vascular disease. J Pathol 2000; 190: 244–54.
Shen YH, Wang XL, Wilcken DE . Nitric oxide induces and inhibits apoptosis through different pathways. FEBS Lett 1998; 433: 125–31.
Walford G, HLoscalzo J . Nitric oxide in vascular biology. J Thromb Haemost 2003; 1: 2112–8.
Rodríguez-Rodríguez R, Herrera MD, de Sotomayor MA, Ruiz-Gutierrez V . Pomace olive oil improves endothelial function in spontaneously hypertensive rats by increasing endothelial nitric oxide synthase expression. Am J Hypertens 2007; 20: 728–34.
Lee CC, Chen PR, Lin S, Tsaia SC, Wanga BW, Chena WW, et al. Sesamin induces nitric oxide and decreases endothelin-1 production in HUVECs: possible implications for its antihypertensive effect. J Hypertens 2004; 22: 2329–38.
Ferroni P, Basili S, Paoletti V, Davì G . Endothelial dysfunction and oxidative stress in arterial hypertension. Nutr Metab Cardiovasc Dis 2006; 16: 222–33.
Harrison DG, Gongora MC, Guzik TJ, Widder J . Oxidative stress and hypertension. J Am Soc Hypertens 2007; 1: 30–44.
Ceriello A . Possible role of oxidative stress in the pathogenesis of hypertension. Diabetes Care 2008; 31: S181–4.
Rodrigo R, Passalacqua W, Araya J, Orellana M, Rivera G . Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension. J Cardiovasc Pharmacol 2003; 42: 453–61.
Becker LB . New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res 2004; 61: 461–70.
Juránek I, Bezek S . Controversy of free radical hypothesis: reactive oxygen species — cause or consequence of tissue injury? Gen Physiol Biophys 2005; 24: 263–78.
Janero DR . Malondialdehyde and thiobarbituric-acid reactivity as diagnostic indices of lipid peroxidation, and peroxidative tissue injury. Free Radic Biol Med 1990; 9: 515–40.
Maxwell SR, Dietrich T, Chapple IL . Prediction of serum total antioxidant activity from the concentration of individual serum antioxidants. Clin Chim Acta 2006; 372: 188–94.
Mueller CF, Laude K, McNally JS, Harrison DG . ATVB in focus: redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol 2005; 25: 274–8.
Strålin P, Karlsson K, Johansson BO, Marklund SL . The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase. Arterioscler Thromb Vasc Biol 1995; 15: 2032–6.
Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS . Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. J Clin Invest 1996; 98: 2572–9.
Halliwell B . Antioxidant defence mechanisms: from the beginning to the end (of the beginning). Free Radic Res 1999; 3: 261–72.
Channon KM, Guzik TJ . Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. J Physiol Pharmacol 2002; 53: 515–24.
Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, et al. Superoxide production and expression of Nox family proteins in human atherosclerosis. Circulation 2002; 105: 1429–35.
Yamawaki H, Haendeler J, Berk BC . Thioredoxin: a key regulator of cardiovascular homeostasis. Circ Res 2003; 93: 1029–33.
Jones SA, O'Donnell VB, Wood JD, Broughton JP, Hughes EJ, Jones OT . Expression of phagocyte NADPH oxidase components in human endothelial cells. Am J Physiol 1996; 271: H1626–34.
Azumi H, Inoue N, Takeshita S, Rikitake Y, Kawashima S, Hayashi Y, et al. Expression of NADH/NADPH oxidase p22phox in human coronary arteries. Circulation 1999; 100: 1494–8.
Griendling KK, Sorescu D, Ushio-Fukai M . NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 2000; 86, 494–501.
Lassègue B, HClempus RE . Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 2003; 285: R277–97.
Tschudi M, Mesaros S, Luscher TF, Malinski T . Direct in situ measurement of nitric oxide in mesenteric resistance arteries: increased decomposition by superoxide in hypertension. Hypertension 1996; 27: 32–5.
List BM, Klösch B, Völker C, Gorren AC, Sessa WC, Werner ER, et al. Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization. Biochem J 1997; 323: 159–65.
Somers MJ, Harrison DG . Reactive oxygen species and the control of vasomotor tone. Curr Hypertens Rep 1999; 1: 102–8.
Yao L, Romero MJ, Toque HA, Yang G, Caldwell RB, Caldwell RW . The role of RhoA/Rho kinase pathway in endothelial dysfunction. J Cardiovasc Dis Res 2010; 1: 165–70.
Cosentino F, Lüscher TF . Tetrahydrobiopterin and endothelial function. Eur Heart J 1998; 19: G3–8.
Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA, et al. Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 2001; 103: 1282–8.
Szabó CH . Multiple pathways of peroxynitrite cytotoxicity. Toxicol Lett 2003; 140: 105–12.
Hong HJ, Loh SH, Yen MH . Suppression of the development of hypertension by the inhibitor of inducible nitric oxide synthase. Br J Pharmacol 2000; 131: 631–7.
Acknowledgements
This work was supported by grants from the Key Program of Natural Science Foundation of Education Department of Anhui Province (No 2006kj099A), the Program of Universities Excellent Young Talent Foundation of Anhui Province (No 2009SQRZ184) and the Young and Middle-aged Research Foundation of Wannan Medical College (No WK201206, WK201212).
Author information
Authors and Affiliations
Corresponding author
PowerPoint slides
Rights and permissions
About this article
Cite this article
Zhang, Jx., Yang, Jr., Chen, Gx. et al. Sesamin ameliorates arterial dysfunction in spontaneously hypertensive rats via downregulation of NADPH oxidase subunits and upregulation of eNOS expression. Acta Pharmacol Sin 34, 912–920 (2013). https://doi.org/10.1038/aps.2013.1
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2013.1
Keywords
This article is cited by
-
Effect of foxtail millet protein hydrolysates on lowering blood pressure in spontaneously hypertensive rats
European Journal of Nutrition (2017)
-
Chronic administration of the probiotic kefir improves the endothelial function in spontaneously hypertensive rats
Journal of Translational Medicine (2015)


