Avenanthramide, a polyphenol from oats, inhibits vascular smooth muscle cell proliferation and enhances nitric oxide production


      The proliferation of vascular smooth muscle cells (SMC) and impaired nitric oxide (NO) production are both crucial pathophysiological processes in the initiation and development of atherosclerosis. Epidemiological data have indicated that diets rich in whole grain foods are associated with a reduced risk of developing atherosclerosis. Avenanthramides are polyphenols found exclusively in oats (Avena sativa L.). The present study was conducted to examine the effect of synthetically prepared avenanthramide-2c on the proliferation of SMC and NO production by SMC and human aortic endothelial cells (HAEC). Avenanthramide-2c significantly inhibited serum-induced SMC proliferation. At a concentration of 120 μM, avenanthramide-2c inhibited more than 50% of SMC proliferation, as measured by [3H] thymidine incorporation, and increased the doubling time of rat SMC line (A10) from 28 to 48 h. Treatment of human SMC with 40, 80, and 120 μM avenanthramide-2c inhibited cell number increase by 41, 62, and 73%, respectively. In addition, avenanthramide-2c treatment significantly and dose-dependently increased NO production in both SMC and HAEC. At a concentration of 120 μM, avenanthramide-2c increased NO production by three-fold in SMC, and by nine-fold in HAEC. These increases were in parallel with the up-regulation of mRNA expression for endothelial NO synthase (eNOS) in both vascular SMC and HAEC. These results suggest that the avenanthramides of oats may contribute to the prevention of atherosclerosis through inhibition of SMC proliferation and increasing NO production.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Koga T.
        • Meydani M.
        Effect of plasma metabolites of (+)-catechin and quercetin on monocyte adhesion to human aortic endothelial cells.
        Am J Clin Nutr. 2001; 73: 941-948
        • Anderson J.W.
        Dietary fibre, complex carbohydrate and coronary artery disease.
        Can J Cardiol. 1995; 11: 55G-62G
        • Katz D.L.
        • Nawaz H.
        • Boukhalil J.
        • et al.
        Effects of oat and wheat cereals on endothelial responses.
        Prev Med. 2001; 33: 476-484
        • Jacobs Jr., D.R.
        • Meyer K.A.
        • Kushi L.H.
        • Folsom A.R.
        Whole-grain intake may reduce the risk of ischemic heart disease death in postmenopausal women: the Iowa Women's Health Study.
        Am J Clin Nutr. 1998; 68: 248-257
        • Anderson J.W.
        • Hanna T.J.
        • Peng X.
        • Kryscio R.J.
        Whole grain foods and heart disease risk.
        J Am Coll Nutr. 2000; 19: 291S-299S
        • Collins F.W.
        Oat phenolics: structure, occurence and function.
        in: Webster F.H. Oats: Chemistry and Technology. American Association of Cereal Chemists, 1986: 227-259
        • Collins F.W.
        Oat phenolics: avenanthramides, novel substituted N-cinnamoylanthranilate alkaloids from oat groats and hulls.
        J Agric Food Chem. 1989; 37: 60-66
        • Collins F.W.
        • McLachlan D.C.
        • Blackwell B.A.
        Oat phenolics: avenalumic acids, a new group of bound phenolics acids from oat groats and hulls.
        Cereal Chem. 1991; 68: 184-189
        • Collins F.W.
        • Mullin W.J.
        High-performance liquid chromatographic deermination of avenanthramides, N-aroylanthranilic acid alkaloids from oats.
        J Chromatogr. 1988; 45: 363-370
        • Peterson D.M.
        • Hahn M.J.
        • Emmons C.L.
        Oat avenanthramides exhibit antioxidant activities in vitro.
        Food Chem. 2002; 79: 473-478
        • Emmons C.L.
        • Peterson D.M.
        Antioxidant activity and phenolic content of oat groats and hulls.
        Cereal Chem. 1999; 76: 902-906
        • Peterson D.M.
        • Emmons C.L.
        • Hibbs A.H.
        Phenolic antioxidants and antioxidant activity in pearling fractions of oat groats.
        J Cereal Sci. 2001; 33: 97-103
        • Emmons C.L.
        • Peterson D.M.
        Antioxidant activity and phenolic content of oat as affected by cultivar and location.
        Crop Sci. 2001; 41: 1676-1681
        • Chen C.Y.
        • Milbury P.E.
        • Kwak H.K.
        • Collins F.W.
        • Samuel P.
        • Blumberg J.B.
        Avenanthramides and phenolic acids from oats are bioavailable and act synergistically with vitamin C to enhance hamster and human LDL resistance to oxidation.
        J Nutr. 2004; 134: 1459-1466
        • Chen C.-Y.
        • Milbury P.E.
        • Li T.
        • O’Leary J.
        • Blumberg J.B.
        Antioxidant capacity and bioavailability of oat avenanthramides.
        FASEB J. 2005; 19: A1477
        • Liu L.
        • Zubik L.
        • Collins F.W.
        • Marko M.
        • Meydani M.
        The antiatherogenic potential of oat phenolic compounds.
        Atherosclerosis. 2004; 175: 39-49
        • Yue T.L.
        • Wang X.
        • Sung C.P.
        • et al.
        Interleukin-8. A mitogen and chemoattractant for vascular smooth muscle cells.
        Circ Res. 1994; 75: 1-7
        • Pieper G.M.
        Review of alterations in endothelial nitric oxide production in diabetes: protective role of arginine on endothelial dysfunction.
        Hypertension. 1998; 31: 1047-1060
        • Felaco M.
        • Grilli A.
        • De Lutiis M.A.
        • et al.
        Endothelial nitric oxide synthase (eNOS) expression and localization in healthy and diabetic rat hearts.
        Ann Clin Lab Sci. 2001; 31: 179-186
      1. Bundy RE, Marczin N, Birks EF, et al. Transplant atherosclerosis: role of phenotypic modulation of vascular smooth muscle by nitric oxide. Gen Pharmacol 2000;34:73–8.

        • Nakatsubo N.
        • Kojima H.
        • Kikuchi K.
        • et al.
        Direct evidence of nitric oxide production from bovine aortic endothelial cells using new fluorescence indicators: diaminofluoresceins.
        FEBS Lett. 1998; 427: 263-266
        • Pandolfi A.
        • Grilli A.
        • Cilli C.
        • et al.
        Phenotype modulation in cultures of vascular smooth muscle cells from diabetic rats: association with increased nitric oxide synthase expression and superoxide anion generation.
        J Cell Physiol. 2003; 196: 378-385
        • Liu S.
        • Manson J.E.
        • Stampfer M.J.
        • et al.
        Whole grain consumption and risk of ischemic stroke in women: a prospective study.
        JAMA. 2000; 284: 1534-1540
        • Rao R.S.
        • Miano J.M.
        • Olson E.N.
        • Seidel C.L.
        The A10 cell line: a model for neonatal, neointimal, or differentiated vascular smooth muscle cells?.
        Cardiovasc Res. 1997; 36: 118-126
        • Locher R.
        • Brandes R.P.
        • Vetter W.
        • Barton M.
        Native LDL induces proliferation of human vascular smooth muscle cells via redox-mediated activation of ERK 1/2 mitogen-activated protein kinases.
        Hypertension. 2002; 39: 645-650
        • Locher R.
        • Emmanuele L.
        • Suter P.M.
        • Vetter W.
        • Barton M.
        Green tea polyphenols inhibit human vascular smooth muscle cell proliferation stimulated by native low-density lipoprotein.
        Eur J Pharmacol. 2002; 434: 1-7
        • Sacca P.
        • Caballero F.
        • Batlle A.
        • Vazquez E.
        Cell cycle arrest and modulation of HO-1 expression induced by acetyl salicylic acid in hepatocarcinogenesis.
        Int J Biochem Cell Biol. 2004; 36: 1945-1953
        • Moon S.K.
        • Cho G.O.
        • Jung S.Y.
        • et al.
        Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metalloproteinase-9.
        Biochem Biophys Res Commun. 2003; 301: 1069-1078
        • Trovati M.
        • Massucco P.
        • Mattiello L.
        • et al.
        Human vascular smooth muscle cells express a constitutive nitric oxide synthase that insulin rapidly activates, thus increasing guanosine 3′:5′-cyclic monophosphate and adenosine 3′:5′-cyclic monophosphate concentrations.
        Diabetologia. 1999; 42: 831-839
        • Papapetropoulos A.
        • Rudic R.D.
        • Sessa W.C.
        Molecular control of nitric oxide synthases in the cardiovascular system.
        Cardiovasc Res. 1999; 43: 509-520
        • Kurihara N.
        • Alfie M.E.
        • Sigmon D.H.
        • Rhaleb N.E.
        • Shesely E.G.
        • Carretero O.A.
        Role of nNOS in blood pressure regulation in eNOS null mutant mice.
        Hypertension. 1998; 32: 856-861
        • Huang P.L.
        • Huang Z.
        • Mashimo H.
        • et al.
        Hypertension in mice lacking the gene for endothelial nitric oxide synthase.
        Nature. 1995; 377: 239-242
        • Ji L.L.
        • Lay D.
        • Chung E.
        • Fu Y.
        • Peterson D.M.
        Effect of avenathramides on oxidant generation and antioxidant enzyme activity in exercised rats.
        Nutr Res. 2003; 23: 1579-1590