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Glucosinolates pp 319-337 | Cite as

Sulforaphane and Atherosclerosis

  • Pon Velayutham Anandh BabuEmail author
  • Chrissa PetersenEmail author
  • Zhenquan JiaEmail author
Reference work entry
Part of the Reference Series in Phytochemistry book series (RSP)

Abstract

Epidemiological studies have found associations between cruciferous vegetable consumption and reduced risk of chronic conditions, such as atherosclerosis, diabetes, and cancer. Sulforaphane, a molecule found in its precursor state in cruciferous and other vegetables, is the focus of much current nutritional interest. Others and we have recently reported the beneficial cardiovascular effects of sulforaphane and the possible molecular mechanisms involved. Sulforaphane improved cardiovascular complications such as vascular inflammation, hypertension, and atherosclerosis in animal models. Evidence shows that sulforaphane may exert the beneficial cardiovascular effects by acting on multiple targets such as (i) activating Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor [erythroid-derived 2]-like 2 (Nrf2) signaling pathway, (ii) inhibiting inflammatory pathways, and (iii) regulating lipid metabolism. However, human studies related to the vascular effects of sulforaphane and cruciferous vegetables are lacking. Hence, well-designed human trials may be needed to evaluate the cardiovascular effects of sulforaphane and cruciferous vegetables and to recommend cruciferous vegetables, to improve cardiovascular health. This chapter provides an overview of recent developments toward the understanding of cardioprotective effects of sulforaphane and the molecular mechanisms involved.

Keywords

Sulforaphane Vascular disease Nrf2 Atherosclerosis Cruciferous vegetables Endothelium Cardioprotective 

Abbreviations

ARE

Antioxidant response element

C/EBP

CCAAT/enhancer-binding protein

CVD

Cardiovascular disease

GCL

Glutamate-cysteine ligase

GCS

γ-Glutamyl cysteine synthetase

GCLC

Glutamate-cysteine ligase catalytic subunit

GCLM

Glutamate-cysteine ligase modifier subunit

GPX

Glutathione peroxidase

GR

Glutathione reductase

GSH

Glutathione-S-transferase

HDL

High-density lipoprotein

HO-1

Heme oxygenase-1

ICAM-1

Intracellular adhesion molecule-1

IĸBα

Inhibitor of NFĸB

IĸKβ

IĸB kinase

IL-8

Interleukin-8

Keap1

Kelch-like ECH-associated protein 1

LDL

Low-density lipoprotein

LPS

Lipopolysaccharide

MAPK

Mitogen-activated protein kinase

MCP-1

Monocyte chemotactic protein-1

NFĸB

Nuclear factor ĸB

NQO1

NADPH quinone oxidoreductase

Nrf2

Nuclear factor [erythroid-derived 2]-like 2

PPARγ

Peroxisome proliferator-activated receptor γ

ROS

Reactive oxygen species

SHRs

Spontaneously hypertensive rats

SHRSP

Spontaneously hypertensive stroke-prone

SMC

Smooth muscle cells

SOD

Superoxide dismutase

TLR

Toll-like receptor

TNF-α

Tumor necrosis factor-α

VCAM-1

Vascular cell adhesion molecule-1

VSMCs

Vascular smooth muscle cells

WKY rats

Wistar Kyoto rats

References

  1. 1.
    Ritchey MD, Wall HK, Gillespie C, George MG, Jamal A, Division for Heart D, Stroke Prevention CDC (2014) Million hearts: prevalence of leading cardiovascular disease risk factors – United States, 2005–2012. MMWR Morb Mortal Wkly Rep 63:462–467Google Scholar
  2. 2.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS et al (2014) Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 129:e28–e292CrossRefGoogle Scholar
  3. 3.
    Luepker RV (2011) Cardiovascular disease: rise, fall, and future prospects. Annu Rev Public Health 32:1–3CrossRefGoogle Scholar
  4. 4.
    Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 27:165–197CrossRefGoogle Scholar
  5. 5.
    Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu KA, Ryder JJ, Hall WL, Cassidy A (2008) Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 88:38–50Google Scholar
  6. 6.
    Mulvihill EE, Huff MW (2010) Antiatherogenic properties of flavonoids: implications for cardiovascular health. Can J Cardiol 26(Suppl A):17A–21ACrossRefGoogle Scholar
  7. 7.
    Erdman JW Jr, Balentine D, Arab L, Beecher G, Dwyer JT, Folts J, Harnly J, Hollman P, Keen CL et al (2007) Flavonoids and heart health: proceedings of the ILSI North America flavonoids workshop, May 31–June 1, 2005, Washington, DC. J Nutr 137:718S–737SGoogle Scholar
  8. 8.
    Beecher GR (2003) Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr 133:3248S–3254SGoogle Scholar
  9. 9.
    Del Rio D, Borges G, Crozier A (2010) Berry flavonoids and phenolics: bioavailability and evidence of protective effects. Br J Nutr 104(Suppl 3):S67–S90Google Scholar
  10. 10.
    Houghton CA, Fassett RG, Coombes JS (2013) Sulforaphane: translational research from laboratory bench to clinic. Nutr Rev 71:709–726CrossRefGoogle Scholar
  11. 11.
    Genkinger JM, Platz EA, Hoffman SC, Comstock GW, Helzlsouer KJ (2004) Fruit, vegetable, and antioxidant intake and all-cause, cancer, and cardiovascular disease mortality in a community-dwelling population in Washington County, Maryland. Am J Epidemiol 160:1223–1233CrossRefGoogle Scholar
  12. 12.
    Lockheart MS, Steffen LM, Rebnord HM, Fimreite RL, Ringstad J, Thelle DS, Pedersen JI, Jacobs DR Jr (2007) Dietary patterns, food groups and myocardial infarction: a case-control study. Br J Nutr 98:380–387CrossRefGoogle Scholar
  13. 13.
    Zhang X, Shu XO, Xiang YB, Yang G, Li H, Gao J, Cai H, Gao YT, Zheng W (2011) Cruciferous vegetable consumption is associated with a reduced risk of total and cardiovascular disease mortality. Am J Clin Nutr 94:240–246CrossRefGoogle Scholar
  14. 14.
    Grover-Paez F, Zavalza-Gomez AB (2009) Endothelial dysfunction and cardiovascular risk factors. Diabetes Res Clin Pract 84:1–10CrossRefGoogle Scholar
  15. 15.
    Su JB (2015) Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 7:719–741CrossRefGoogle Scholar
  16. 16.
    Chistiakov DA, Orekhov AN, Bobryshev YV (2015) Endothelial barrier and its abnormalities in cardiovascular disease. Front Physiol 6:365CrossRefGoogle Scholar
  17. 17.
    Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y et al (2003) Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association. Circulation 107:499–511CrossRefGoogle Scholar
  18. 18.
    Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC (1995) Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 332:635–641CrossRefGoogle Scholar
  19. 19.
    Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V (2004) C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 50:1387–1397CrossRefGoogle Scholar
  20. 20.
    Ridker PM, Hennekens CH, Buring JE, Rifai N (2000) C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836–843CrossRefGoogle Scholar
  21. 21.
    Yin G, Yang X, Li B, Yang M, Ren M (2014) Connexin43 siRNA promotes HUVEC proliferation and inhibits apoptosis induced by ox-LDL: an involvement of ERK signaling pathway. Mol Cell Biochem 394:101–107CrossRefGoogle Scholar
  22. 22.
    Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874CrossRefGoogle Scholar
  23. 23.
    Nallasamy P, Si H, Babu PV, Pan D, Fu Y, Brooke EA, Shah H, Zhen W, Zhu H et al (2014) Sulforaphane reduces vascular inflammation in mice and prevents TNF-alpha-induced monocyte adhesion to primary endothelial cells through interfering with the NF-kappaB pathway. J Nutr Biochem 25:824–833CrossRefGoogle Scholar
  24. 24.
    Ye L, Dinkova-Kostova AT, Wade KL, Zhang Y, Shapiro TA, Talalay P (2002) Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta 316:43–53CrossRefGoogle Scholar
  25. 25.
    Latte KP, Appel KE, Lampen A (2011) Health benefits and possible risks of broccoli – an overview. Food Chem Toxicol 49:3287–3309CrossRefGoogle Scholar
  26. 26.
    Cornelis MC, El-Sohemy A, Campos H (2007) GSTT1 genotype modifies the association between cruciferous vegetable intake and the risk of myocardial infarction. Am J Clin Nutr 86:752–758Google Scholar
  27. 27.
    Senanayake GV, Banigesh A, Wu L, Lee P, Juurlink BH (2012) The dietary phase 2 protein inducer sulforaphane can normalize the kidney epigenome and improve blood pressure in hypertensive rats. Am J Hypertens 25:229–235CrossRefGoogle Scholar
  28. 28.
    Wu L, Noyan Ashraf MH, Facci M, Wang R, Paterson PG, Ferrie A, Juurlink BH (2004) Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system. Proc Natl Acad Sci U S A 101:7094–7099CrossRefGoogle Scholar
  29. 29.
    Bai Y, Cui W, Xin Y, Miao X, Barati MT, Zhang C, Chen Q, Tan Y, Cui T et al (2013) Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation. J Mol Cell Cardiol 57:82–95CrossRefGoogle Scholar
  30. 30.
    Zhang Z, Wang S, Zhou S, Yan X, Wang Y, Chen J, Mellen N, Kong M, Gu J et al (2014) Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway. J Mol Cell Cardiol 77:42–52CrossRefGoogle Scholar
  31. 31.
    Dhalla NS, Temsah RM, Netticadan T (2000) Role of oxidative stress in cardiovascular diseases. J Hypertens 18:655–673CrossRefGoogle Scholar
  32. 32.
    Park KH, Park WJ (2015) Endothelial dysfunction: clinical implications in cardiovascular disease and therapeutic approaches. J Korean Med Sci 30:1213–1225CrossRefGoogle Scholar
  33. 33.
    Babu PV, Liu D (2008) Green tea catechins and cardiovascular health: an update. Curr Med Chem 15:1840–1850CrossRefGoogle Scholar
  34. 34.
    Villeneuve NF, Lau A, Zhang DD (2010) Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases. Antioxid Redox Signal 13:1699–1712CrossRefGoogle Scholar
  35. 35.
    Kensler TW, Egner PA, Agyeman AS, Visvanathan K, Groopman JD, Chen JG, Chen TY, Fahey JW, Talalay P (2013) Keap1-nrf2 signaling: a target for cancer prevention by sulforaphane. Top Curr Chem 329:163–177CrossRefGoogle Scholar
  36. 36.
    Kwon JS, Joung H, Kim YS, Shim YS, Ahn Y, Jeong MH, Kee HJ (2012) Sulforaphane inhibits restenosis by suppressing inflammation and the proliferation of vascular smooth muscle cells. Atherosclerosis 225:41–49CrossRefGoogle Scholar
  37. 37.
    Miao X, Bai Y, Sun W, Cui W, Xin Y, Wang Y, Tan Y, Miao L, Fu Y et al (2012) Sulforaphane prevention of diabetes-induced aortic damage was associated with the up-regulation of Nrf2 and its down-stream antioxidants. Nutr Metabol 9:84CrossRefGoogle Scholar
  38. 38.
    Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278:8135–8145CrossRefGoogle Scholar
  39. 39.
    Yang YM, Noh K, Han CY, Kim SG (2010) Transactivation of genes encoding for phase II enzymes and phase III transporters by phytochemical antioxidants. Molecules 15:6332–6348CrossRefGoogle Scholar
  40. 40.
    Stefanson AL, Bakovic M (2014) Dietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals. Nutrients 6:3777–3801CrossRefGoogle Scholar
  41. 41.
    Velmurugan GV, Sundaresan NR, Gupta MP, White C (2013) Defective Nrf2-dependent redox signalling contributes to microvascular dysfunction in type 2 diabetes. Cardiovasc Res 100:143–150CrossRefGoogle Scholar
  42. 42.
    Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62:5196–5203Google Scholar
  43. 43.
    Balligand JL (2013) Reducing damage through Nrf-2. Cardiovasc Res 100:1–3CrossRefGoogle Scholar
  44. 44.
    Chapple SJ, Siow RC, Mann GE (2012) Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. Int J Biochem Cell Biol 44:1315–1320CrossRefGoogle Scholar
  45. 45.
    Zakkar M, Van der Heiden K, le Luong A, Chaudhury H, Cuhlmann S, Hamdulay SS, Krams R, Edirisinghe I, Rahman I et al (2009) Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state. Arterioscler Thromb Vasc Biol 29:1851–1857CrossRefGoogle Scholar
  46. 46.
    Huang CS, Lin AH, Liu CT, Tsai CW, Chang IS, Chen HW, Lii CK (2013) Isothiocyanates protect against oxidized LDL-induced endothelial dysfunction by upregulating Nrf2-dependent antioxidation and suppressing NFκB activation. Mol Nutr Food Res 57:1918–1930CrossRefGoogle Scholar
  47. 47.
    Rizzo B, Maltese G, Paraskevi MP, Hrelia S, Mann G, Siow R (2014) Induction of antioxidant genes by sulforaphane and klotho in human aortic smooth muscle cells. Free Radic Biol Med 75(Suppl 1):S14–S15CrossRefGoogle Scholar
  48. 48.
    Wu L, Juurlink BH (2001) The impaired glutathione system and its up-regulation by sulforaphane in vascular smooth muscle cells from spontaneously hypertensive rats. J Hypertens 19:1819–1825CrossRefGoogle Scholar
  49. 49.
    Juurlink BH (2001) Therapeutic potential of dietary phase 2 enzyme inducers in ameliorating diseases that have an underlying inflammatory component. Can J Physiol Pharmacol 79:266–282CrossRefGoogle Scholar
  50. 50.
    Lopes RA, Neves KB, Tostes RC, Montezano AC, Touyz RM (2015) Downregulation of nuclear factor erythroid 2-related factor and associated antioxidant genes contributes to redox-sensitive vascular dysfunction in hypertension. Hypertension 66:1240–1250Google Scholar
  51. 51.
    Menzaghi C, Bacci S, Salvemini L, Mendonca C, Palladino G, Fontana A, De Bonis C, Marucci A, Goheen E et al (2013) Serum resistin, cardiovascular disease and all-cause mortality in patients with type 2 diabetes. PLoS One 8:e64729CrossRefGoogle Scholar
  52. 52.
    Whelton A (2006) Clinical implications of nonopioid analgesia for relief of mild-to-moderate pain in patients with or at risk for cardiovascular disease. Am J Cardiol 97:3–9CrossRefGoogle Scholar
  53. 53.
    Pearson TA, Mensah GA, Hong Y, Smith SC Jr (2004) CDC/AHA workshop on markers of inflammation and cardiovascular disease: application to clinical and public health practice: overview. Circulation 110:e543–e544CrossRefGoogle Scholar
  54. 54.
    Paneni F, Beckman JA, Creager MA, Cosentino F (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 34:2436–2443CrossRefGoogle Scholar
  55. 55.
    Shirwany NA, Zou MH (2012) Vascular inflammation is a missing link for diabetes-enhanced atherosclerotic cardiovascular diseases. Front Biosci 17:1140–1164CrossRefGoogle Scholar
  56. 56.
    Frangogiannis NG (2008) The immune system and cardiac repair. Pharmacol Res 58:88–111CrossRefGoogle Scholar
  57. 57.
    Savoia C, Schiffrin EL (2007) Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci 112:375–384CrossRefGoogle Scholar
  58. 58.
    Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J et al (2004) A physical and functional map of the human TNF-alpha/NFκ B signal transduction pathway. Nat Cell Biol 6:97–105CrossRefGoogle Scholar
  59. 59.
    Kim F, Tysseling KA, Rice J, Gallis B, Haji L, Giachelli CM, Raines EW, Corson MA, Schwartz MW (2005) Activation of Iκbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. J Mol Cell Cardiol 39:327–334CrossRefGoogle Scholar
  60. 60.
    Yerneni KK, Bai W, Khan BV, Medford RM, Natarajan R (1999) Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells. Diabetes 48:855–864CrossRefGoogle Scholar
  61. 61.
    Bartchewsky W Jr, Martini MR, Masiero M, Squassoni AC, Alvarez MC, Ladeira MS, Salvatore D, Trevisan M, Pedrazzoli J Jr, Ribeiro ML (2009) Effect of Helicobacter pylori infection on IL-8, IL-1beta and COX-2 expression in patients with chronic gastritis and gastric cancer. Scand J Gastroenterol 44:153–161CrossRefGoogle Scholar
  62. 62.
    Shan Y, Lin N, Yang X, Tan J, Zhao R, Dong S, Wang S (2012) Sulphoraphane inhibited the expressions of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 through MyD88-dependent toll-like receptor-4 pathway in cultured endothelial cells. Nutr Metab Cardiovasc Dis 22:215–222CrossRefGoogle Scholar
  63. 63.
    Hung CN, Huang HP, Wang CJ, Liu KL, Lii CK (2014) Sulforaphane inhibits TNF-alpha-induced adhesion molecule expression through the Rho A/ROCK/NF-kappaB signaling pathway. J Med Food 17:1095–1102CrossRefGoogle Scholar
  64. 64.
    Chen XL, Dodd G, Kunsch C (2009) Sulforaphane inhibits TNF-alpha-induced activation of p38 MAP kinase and VCAM-1 and MCP-1 expression in endothelial cells. Inflamm Res 58:513–521CrossRefGoogle Scholar
  65. 65.
    Kim JY, Park HJ, Um SH, Sohn EH, Kim BO, Moon EY, Rhee DK, Pyo S (2012) Sulforaphane suppresses vascular adhesion molecule-1 expression in TNF-alpha-stimulated mouse vascular smooth muscle cells: involvement of the MAPK, NF-kappaB and AP-1 signaling pathways. Vasc Pharmacol 56:131–141CrossRefGoogle Scholar
  66. 66.
    Hopkins PN (2013) Molecular biology of atherosclerosis. Physiol Rev 93:1317–1542CrossRefGoogle Scholar
  67. 67.
    Choi KM, Lee YS, Sin DM, Lee S, Lee MK, Lee YM, Hong JT, Yun YP, Yoo HS (2012) Sulforaphane inhibits mitotic clonal expansion during adipogenesis through cell cycle arrest. Obesity 20:1365–1371CrossRefGoogle Scholar
  68. 68.
    Choi KM, Lee YS, Kim W, Kim SJ, Shin KO, Yu JY, Lee MK, Lee YM, Hong JT et al (2014) Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice. J Nutr Biochem 25:201–207CrossRefGoogle Scholar
  69. 69.
    Kivela AM, Makinen PI, Jyrkkanen HK, Mella-Aho E, Xia Y, Kansanen E, Leinonen H, Verma IM, Yla-Herttuala S, Levonen AL (2010) Sulforaphane inhibits endothelial lipase expression through NF-kappaB in endothelial cells. Atherosclerosis 213:122–128CrossRefGoogle Scholar
  70. 70.
    Badellino KO, Wolfe ML, Reilly MP, Rader DJ (2008) Endothelial lipase is increased in vivo by inflammation in humans. Circulation 117:678–685CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of Nutrition and Integrative Physiology, College of HealthUniversity of UtahSalt Lake CityUSA
  2. 2.Department of BiologyUniversity of North Carolina at GreensboroGreensboroUSA

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