European Journal of Nutrition

, Volume 52, Issue 3, pp 1145–1155 | Cite as

Chronic cranberry juice consumption restores cholesterol profiles and improves endothelial function in ovariectomized rats

  • Lai-Ming Yung
  • Xiao Yu Tian
  • Wing Tak Wong
  • Fung Ping Leung
  • Lai Hang Yung
  • Zhen Yu Chen
  • Chi Wai Lau
  • Paul M. Vanhoutte
  • Xiaoqiang Yao
  • Yu Huang
Original Contribution



Postmenopausal women experience higher risks for cardiovascular diseases than age-matched men and pre-menopausal women. There is a need for better treatment strategy for estrogen-deficient-related cardiovascular complications. We and others have recently reported that activated renin–angiotensin system and the associated oxidative stress impaired endothelium-dependent relaxation in ovariectomized rat, while angiotensin receptor blocker rescues endothelial dysfunction. Dietary supplements and lifestyle modifications provide an alternative way to improve cardiovascular health. The present study tests the hypothesis that chronic cranberry juice consumption improves cholesterol profiles and vascular functions in estrogen-deficient animal model. The effect of cranberry consumption on expression and activity of renin–angiotensin system in the vasculature will be determined.


Ovariectomized rats were treated daily with commercial cranberry juice at 7 mg/kg for 8 weeks, a dosage comparable to recent clinical studies. Serum was collected for measuring cholesterol levels while aorta was isolated for isometric force assay and expression studies.


Cranberry juice consumption reduced circulating levels of total cholesterol, triacylglycerols, HDL, nHDL, and nHDL/HDL ratio. Meanwhile, cranberry juice consumption improved endothelium-dependent relaxation in aorta of ovariectomized rats by restoring p-eNOS level (endothelial nitric oxide synthase phosphorylated at ser-1177), reversing the up-regulated levels of renin–angiotensin system markers (angiotensin-converting enzyme, angiotensin II, and angiotensin II type 1 receptor), and normalizing the elevated NAD(P)H oxidase expression and oxidative stress.


Our data demonstrate the novel cardiovascular benefits of cranberry juice consumption in improving both vascular functions and cholesterol profiles, providing insight into developing cranberry products into useful dietary supplements for postmenopausal women.


Cranberry Estrogen deficiency Nitric oxide Oxidative stress Renin–angiotensin system Endothelial functions 



This work was supported by Hong Kong General Research Fund (CUHK 465308) and CUHK Focused Investment Scheme.

Supplementary material

394_2012_425_MOESM1_ESM.doc (127 kb)
Supplementary material 1 (DOC 127 kb)


  1. 1.
    Wenger NK, Speroff L, Packard B (1993) Cardiovascular health and disease in women. N Engl J Med 329:247–256. doi: 10.1056/NEJM199307223290406 CrossRefGoogle Scholar
  2. 2.
    Rossi R, Nuzzo A, Olaru AI, Origliani G, Modena MG (2011) Endothelial function affects early carotid atherosclerosis progression in hypertensive postmenopausal women. J Hypertens 29:1136–1144. doi: 10.1097/HJH.0b013e328345d950 CrossRefGoogle Scholar
  3. 3.
    Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH (1987) Menopause and the risk of coronary heart disease in women. N Engl J Med 316:1105–1110. doi: 10.1056/NEJM198704303161801 CrossRefGoogle Scholar
  4. 4.
    Kawano H, Yasue H, Hirai N, Yoshida T, Fukushima H, Miyamoto S, Kojima S, Hokamaki J, Nakamura H, Yodoi J, Ogawa H (2003) Effects of transdermal and oral estrogen supplementation on endothelial function, inflammation and cellular redox state. Int J Clin Pharmacol Ther 41:346–353Google Scholar
  5. 5.
    McSorley PT, Young IS, Bell PM, Fee JP, McCance DR (2003) Vitamin C improves endothelial function in healthy estrogen-deficient postmenopausal women. Climacteric 6:238–247Google Scholar
  6. 6.
    Mirza FS, Ong P, Collins P, Okamura K, Gerhard-Herman M, Williams GH, Seely EW (2008) Effects of estradiol and the angiotensin II receptor blocker irbesartan on vascular function in postmenopausal women. Menopause 15:44–50. doi: 10.1097/gme.0b013e318150d13e00042192-200815010-00010 CrossRefGoogle Scholar
  7. 7.
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333CrossRefGoogle Scholar
  8. 8.
    Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, McNabb MA, Wenger NK (2006) Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 355:125–137. doi: 10.1056/NEJMoa062462 CrossRefGoogle Scholar
  9. 9.
    Fernandez-Vega F, Abellan J, Vegazo O, De Vinuesa SG, Rodriguez JC, Maceira B, de Castro SS, Nicolas RR, Luno J (2002) Angiotensin II type 1 receptor blockade to control blood pressure in postmenopausal women: influence of hormone replacement therapy. Kidney Int Suppl:S36–41. Doi: 10.1046/j.1523-1755.62.s82.8.x
  10. 10.
    Wong CM, Yung LM, Leung FP, Tsang SY, Au CL, Chen ZY, Yao X, Cheng CH, Lau CW, Gollasch M, Huang Y (2008) Raloxifene protects endothelial cell function against oxidative stress. Br J Pharmacol 155:326–334. doi: 10.1038/bjp.2008.262 CrossRefGoogle Scholar
  11. 11.
    Yung LM, Wong WT, Tian XY, Leung FP, Yung LH, Chen ZY, Yao X, Lau CW, Huang Y (2011) Inhibition of Renin–Angiotensin system reverses endothelial dysfunction and oxidative stress in estrogen deficient rats. PLoS One 6:e17437. doi: 10.1371/journal.pone.0017437 CrossRefGoogle Scholar
  12. 12.
    Abu-Taha M, Rius C, Hermenegildo C, Noguera I, Cerda-Nicolas JM, Issekutz AC, Jose PJ, Cortijo J, Morcillo EJ, Sanz MJ (2009) Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan. J Immunol 183:1393–1402. doi: 10.4049/jimmunol.0803157 CrossRefGoogle Scholar
  13. 13.
    Nasca MM, Zhou JR, Welty FK (2008) Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women. Am J Cardiol 102:84–86. doi: 10.1016/j.amjcard.2008.02.100 CrossRefGoogle Scholar
  14. 14.
    Hall WL, Formanuik NL, Harnpanich D, Cheung M, Talbot D, Chowienczyk PJ, Sanders TA (2008) A meal enriched with soy isoflavones increases nitric oxide-mediated vasodilation in healthy postmenopausal women. J Nutr 138:1288–1292Google Scholar
  15. 15.
    Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong CP, Nettleton JA, Jacobs DR Jr (2007) Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr 85:895–909Google Scholar
  16. 16.
    Chong MF, Macdonald R, Lovegrove JA (2010) Fruit polyphenols and CVD risk: a review of human intervention studies. Br J Nutr 104(Suppl 3):S28–S39CrossRefGoogle Scholar
  17. 17.
    Arts IC, Jacobs DR Jr, Harnack LJ, Gross M, Folsom AR (2001) Dietary catechins in relation to coronary heart disease death among postmenopausal women. Epidemiology 12:668–675CrossRefGoogle Scholar
  18. 18.
    Rasmussen SE, Frederiksen H, Struntze Krogholm K, Poulsen L (2005) Dietary proanthocyanidins: occurrence, dietary intake, bioavailability, and protection against cardiovascular disease. Mol Nutr Food Res 49:159–174. doi: 10.1002/mnfr.200400082 CrossRefGoogle Scholar
  19. 19.
    Dohadwala MM, Holbrook M, Hamburg NM, Shenouda SM, Chung WB, Titas M, Kluge MA, Wang N, Palmisano J, Milbury PE, Blumberg JB, Vita JA (2011) Effects of cranberry juice consumption on vascular function in patients with coronary artery disease. Am J Clin Nutr 93:934–940. doi: 10.3945/ajcn.110.004242 CrossRefGoogle Scholar
  20. 20.
    Lee IT, Chan YC, Lin CW, Lee WJ, Sheu WH (2008) Effect of cranberry extracts on lipid profiles in subjects with Type 2 diabetes. Diabet Med 25:1473–1477. doi: 10.1111/j.1464-5491.2008.02588.x CrossRefGoogle Scholar
  21. 21.
    Basu A, Betts NM, Ortiz J, Simmons B, Wu M, Lyons TJ (2011) Low-energy cranberry juice decreases lipid oxidation and increases plasma antioxidant capacity in women with metabolic syndrome. Nutr Res 31:190–196. doi: 10.1016/j.nutres.2011.02.003 CrossRefGoogle Scholar
  22. 22.
    Ruel G, Pomerleau S, Couture P, Lemieux S, Lamarche B, Couillard C (2006) Favourable impact of low-calorie cranberry juice consumption on plasma HDL-cholesterol concentrations in men. Br J Nutr 96:357–364CrossRefGoogle Scholar
  23. 23.
    Morales DE, McGowan KA, Grant DS, Maheshwari S, Bhartiya D, Cid MC, Kleinman HK, Schnaper HW (1995) Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91:755–763CrossRefGoogle Scholar
  24. 24.
    Skarsgard P, van Breemen C, Laher I (1997) Estrogen regulates myogenic tone in pressurized cerebral arteries by enhanced basal release of nitric oxide. Am J Physiol 273:H2248–2256Google Scholar
  25. 25.
    Bucolo G, David H (1973) Quantitative determination of serum triacylglycerols by the use of enzymes. Clin Chem 19:476–482Google Scholar
  26. 26.
    Guan L, Yeung SY, Huang Y, Chen ZY (2006) Both soybean and kudzu phytoestrogens modify favorably the blood lipoprotein profile in ovariectomized and castrated hamsters. J Agric Food Chem 54:4907–4912. doi: 10.1021/jf060709a CrossRefGoogle Scholar
  27. 27.
    Zhang L, Fishman MC, Huang PL (1999) Estrogen mediates the protective effects of pregnancy and chorionic gonadotropin in a mouse model of vascular injury. Arterioscler Thromb Vasc Biol 19:2059–2065CrossRefGoogle Scholar
  28. 28.
    Yurino H, Ishikawa S, Sato T, Akadegawa K, Ito T, Ueha S, Inadera H, Matsushima K (2004) Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. Toxicol Sci 81:139–147. doi: 10.1093/toxsci/kfh179kfh179 CrossRefGoogle Scholar
  29. 29.
    Chen H, Zuo Y, Deng Y (2001) Separation and determination of flavonoids and other phenolic compounds in cranberry juice by high-performance liquid chromatography. J Chromatogr A 913:387–395CrossRefGoogle Scholar
  30. 30.
    Valentova K, Stejskal D, Bednar P, Vostalova J, Cihalik C, Vecerova R, Koukalova D, Kolar M, Reichenbach R, Sknouril L, Ulrichova J, Simanek V (2007) Biosafety, antioxidant status, and metabolites in urine after consumption of dried cranberry juice in healthy women: a pilot double-blind placebo-controlled trial. J Agric Food Chem 55:3217–3224. doi: 10.1021/jf0636014 CrossRefGoogle Scholar
  31. 31.
    Jass J, Reid G (2009) Effect of cranberry drink on bacterial adhesion in vitro and vaginal microbiota in healthy females. Can J Urol 16:4901–4907Google Scholar
  32. 32.
    McMurdo ME, Argo I, Phillips G, Daly F, Davey P (2009) Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J Antimicrob Chemother 63:389–395. doi: 10.1093/jac/dkn489 CrossRefGoogle Scholar
  33. 33.
    Efros M, Bromberg W, Cossu L, Nakeleski E, Katz AE (2010) Novel concentrated cranberry liquid blend, UTI-STAT with Proantinox, might help prevent recurrent urinary tract infections in women. Urology 76:841–845. doi: 10.1016/j.urology.2010.01.068 CrossRefGoogle Scholar
  34. 34.
    Howell AB (2007) Bioactive compounds in cranberries and their role in prevention of urinary tract infections. Mol Nutr Food Res 51:732–737. doi: 10.1002/mnfr.200700038 CrossRefGoogle Scholar
  35. 35.
    Jepson RG, Craig JC (2007) A systematic review of the evidence for cranberries and blueberries in UTI prevention. Mol Nutr Food Res 51:738–745. doi: 10.1002/mnfr.200600275 CrossRefGoogle Scholar
  36. 36.
    Neto CC (2007) Cranberry and blueberry: evidence for protective effects against cancer and vascular diseases. Mol Nutr Food Res 51:652–664. doi: 10.1002/mnfr.200600279 CrossRefGoogle Scholar
  37. 37.
    Bayorh MA, Ganafa AA, Eatman D, Walton M, Feuerstein GZ (2005) Simvastatin and losartan enhance nitric oxide and reduce oxidative stress in salt-induced hypertension. Am J Hypertens 18:1496–1502. doi: 10.1016/j.amjhyper.2005.05.022 CrossRefGoogle Scholar
  38. 38.
    Crosswhite P, Sun Z (2010) Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens 28:201–212. doi: 10.1097/HJH.0b013e328332bcdb CrossRefGoogle Scholar
  39. 39.
    Hamilton C (2002) Nitric oxide, oxidative stress and hypertension: a complex equation. J Hypertens 20:1055–1056CrossRefGoogle Scholar
  40. 40.
    Rossi R, Nuzzo A, Origliani G, Modena MG (2008) Metabolic syndrome affects cardiovascular risk profile and response to treatment in hypertensive postmenopausal women. Hypertension 52:865–872. doi: 10.1161/HYPERTENSIONAHA.108.110478 CrossRefGoogle Scholar
  41. 41.
    Stevenson J, Samsioe G, Pines A, Huber J, Netelenbos C, de Roo G, Sitruk-Ware R, Barentsen R, Palacios S, Koninckx PR (1998) Critical comments on the paper—“Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women” by Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Published in: JAMA 1998; 280; 605–613, p. 77–87Google Scholar
  42. 42.
    Wilson T, Luebke JL, Morcomb EF, Carrell EJ, Leveranz MC, Kobs L, Schmidt TP, Limburg PJ, Vorsa N, Singh AP (2011) Glycemic responses to sweetened dried and raw cranberries in humans with type 2 diabetes. J Food Sci 75:H218–H223CrossRefGoogle Scholar
  43. 43.
    Hsu CL, Yen GC (2007) Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats. Br J Nutr 98:727–735. doi: 10.1017/S000711450774686X CrossRefGoogle Scholar
  44. 44.
    Osada K, Takahashi M, Hoshina S, Nakamura M, Nakamura S, Sugano M (2001) Tea catechins inhibit cholesterol oxidation accompanying oxidation of low density lipoprotein in vitro. Comp Biochem Physiol C Toxicol Pharmacol 128:153–164CrossRefGoogle Scholar
  45. 45.
    Schneider MP, Schmidt BM, John S, Schmieder RE (2011) Effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with arterial hypertension and normal cholesterol levels. J Hypertens 29:1757–1764. doi: 10.1097/HJH.0b013e32834a509a CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Lai-Ming Yung
    • 1
    • 2
    • 5
  • Xiao Yu Tian
    • 1
    • 2
  • Wing Tak Wong
    • 1
    • 2
  • Fung Ping Leung
    • 1
    • 2
  • Lai Hang Yung
    • 1
    • 2
  • Zhen Yu Chen
    • 3
  • Chi Wai Lau
    • 1
    • 2
  • Paul M. Vanhoutte
    • 4
  • Xiaoqiang Yao
    • 1
    • 2
  • Yu Huang
    • 1
    • 2
  1. 1.Institute of Vascular Medicine, Li Ka Shing Institute of Health SciencesChinese University of Hong KongHong KongChina
  2. 2.School of Biomedical SciencesChinese University of Hong KongHong KongChina
  3. 3.School of Life SciencesChinese University of Hong KongHong KongChina
  4. 4.Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of MedicineUniversity of Hong KongHong KongChina
  5. 5.Department of Medicine, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations