Skip to main content
SpringerLink
Log in

ACE-inhibitory activity and ACE-inhibiting peptides in different cheese varieties

ACE ACE

Activité inhibitrice et peptides inhibiteurs de l’ACE dans différentes sortes de fromage

  • Review
  • Published:
Dairy Science & Technology

Abstract

During the ripening of cheese, a large number of peptides are formed from casein. Some of these peptides have been shown to exert an antihypertensive effect due to their angiotensin-I-converting enzyme (ACE)-inhibitory activity. Recently, several studies have investigated the ACE-inhibiting potential of cheese, and various ACE-inhibiting peptides have been isolated and identified from different cheese varieties. The present review focuses on the occurrence of two tripeptides, Val-Pro-Pro and Ile-Pro-Pro, in cheese. These tripeptides were first described in fermented-milk products and have been demonstrated to exert a blood pressure-lowering effect in humans with mild hypertension. The influence of cheesemaking and ripening on the release of ACE-inhibiting peptides is revealed. Finally, the antihypertensive potential of cheese with high ACE-inhibitory activity is discussed with regard to the bioavailability of the peptides involved.

Abstract

I (ACE) ACE ACE Val-Pro-Pro (VPP) Ile-Pro-Pro (IPP) ACE ACE

Résumé

Au cours de la maturation du fromage, un grand nombre de peptides sont formés à partir de la caséine. Quelques-uns d’entre eux sont réputés exercer des effets antihypertenseurs en raison de l’activité inhibitrice de l’enzyme de conversion de l’angiotensine I (ACE). Récemment, plusieurs études ont examiné le potentiel inhibiteur d’ACE du fromage, et divers peptides inhibiteurs de l’ACE ont été isolés de différentes sortes de fromage puis identifiés. La présente revue porte sur la présence de deux tripeptides Val-Pro-Pro (VPP) et Ile-Pro-Pro (IPP) dans le fromage. Ces tripeptides sont parmi les premiers à avoir été décrits dans les produits laitiers fermentés et sont réputés exercer un effet antihypertenseur chez les patients présentant une légère hypertension. Cette revue porte aussi sur l’influence de la fabrication et de l’affinage du fromage sur la libération des peptides inhibiteurs de l’ACE, sur le potentiel antihypertenseur du fromage avec une activité inhibitrice élevée de l’ACE de même que la biodisponibilité des peptides en question.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

ACE:

angiotensin-converting enzyme

CN:

casein

DBP:

diastolic blood pressure

FAPGG:

furanacryloyl-phenylalanyl-glycyl-glycine

HHL:

hippuryl-histidyl-leucyl-OH

HPLC:

high-performance liquid chromatography

IPP:

isoleucyl-prolyl-proline

MS:

mass spectrometry

SBP:

systolic blood pressure

SHR:

spontaneously hypertensive rats

VPP:

valyl-prolyl-proline

References

  1. Addeo F., Chianese L., Sacchi R., Musso S.S., Ferranti P., Malorni A., Characterization of the oligopeptides of Parmigiano-Reggiano cheese soluble in 120 g trichloroacetic acid, J. Dairy Res. 61 (1994) 365–374.

    CAS  Google Scholar 

  2. Ai L.Z., Guo B.H., Zhang H., Wu Z.J., Chen W., Wang Y.Y., Tang J.A., Isolation and antihypertensive effect of exopolysaccharides from Lactobacillus casei LC2W, Milchwissenschaft-Milk Sci. Int. 63 (2008) 3–6.

    CAS  Google Scholar 

  3. Aihara K., Kajimoto O., Hirata H., Takahashi R., Nakamura Y., Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension, J. Am. Coll. Nutr. 24 (2005) 257–265.

    Google Scholar 

  4. Apostolidis E., Kwon Y.I., Shetty K., Inhibitory potential of herb, fruit, and fungal-enriched cheese against key enzymes linked to type 2 diabetes and hypertension, Innovat. Food Sci. Emerg. Technol. 8 (2007) 46–54.

    CAS  Google Scholar 

  5. Appel L.J., Moore T.J., Obarzanek E., Vollmer W.M., Svetkey L.P., Sacks F.M., Bray G.A., Vogt T.M., Cutler J.A., Windhauser M.M., Lin P.H., Karanja N., A clinical trial of the effects of dietary patterns on blood pressure, N. Engl. J. Med. 336 (1997) 1117–1124.

    CAS  Google Scholar 

  6. Ashar M.N., Chand R., Antihypertensive peptides purified from milks fermented with Lactobacillus delbrueckii ssp. bulgaricus, Milchwissenschaft-Milk Sci. Int. 59 (2004) 14–17.

    CAS  Google Scholar 

  7. Bachmann H.P., Bütikofer U., Badertscher R., Dalla Torre M., Lavanchy P., Bühler-Moor U., Nick B., Jimeno J., Warmke R., Grosch W., Sieber R., Bosset J.O., Reifungsverlauf von in Folien verpacktem Emmentaler Käse mit und ohne Zusatz von Lactobacillus casei subsp. casei. I. Mikrobiologische, chemische, rheologische und sensorische Untersuchungen, Lebensm.-Wiss. Technol. 30 (1997) 417–428.

    CAS  Google Scholar 

  8. Bachmann H.P., Bütikofer U., Meyer J., Prediction of flavour and texture development in Swiss-type cheeses, Food Sci. Technol.-Lebensm.-Wiss. Technol. 32 (1999) 284–289.

    CAS  Google Scholar 

  9. Bachmann H.P., Bütikofer U., Sieber R., Über das Vorkommen von bioaktiven Peptiden in Käse, Mitt. Lebensmittelunters. Hyg. 94 (2003) 136–154.

    CAS  Google Scholar 

  10. Bernard B.K., Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): I. Executive summary, Int. J. Toxicol. 24 (2005) 1–3.

    Google Scholar 

  11. Bernard B.K., Nakamura Y., Aihara K., Mennear J.H., Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): IX. Evaluation of the mutagenic potential of synthesized L-valyl-L-prolyl-L-proline in the Salmonella-Escherichia coli/microsome, incorporation assay, Int. J. Toxicol. 24 (2005) 107–113.

    CAS  Google Scholar 

  12. Bernard B.K., Nakamura Y., Bando I., Mennear J.H., Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): II. Introduction, Int. J. Toxicol. 24 (2005) 5–11.

    CAS  Google Scholar 

  13. Boelsma E., Kloek J., Lactotripeptides and antihypertensive effects: a critical review, Br. J. Nutr. 101 (2009) 776–786.

    CAS  Google Scholar 

  14. Bütikofer U., Baumann E., Sieber R., Bosset J.O., Ripening of Emmental cheese wrapped in foil with and without addition of Lactobacillus casei subsp. casei. IV. HPLC separation of water soluble peptides, Food Sci. Technol.-Lebensm.-Wiss. Technol. 31 (1998) 297–301.

    Google Scholar 

  15. Bütikofer U., Meyer J., Sieber R., Walther B., Wechsler D., Occurrence of the angiotensin-converting enzyme-inhibiting tripeptides Val-Pro-Pro and Ile-Pro-Pro in different cheese varieties of Swiss origin, J. Dairy Sci. 91 (2008) 29–38.

    Google Scholar 

  16. Bütikofer U., Meyer J., Sieber R., Wechsler D., Quantification of the angiotensin-converting enzmye-inhibiting tripeptides Val-Pro-Pro and Ile-Pro-Pro in hard, semi-hard and soft cheeses, Int. Dairy J. 17 (2007) 968–975.

    Google Scholar 

  17. Cadée J.A., Chang C.Y., Chen C.W., Huang C.N., Chen S.L., Wang C.K., Bovine casein hydrolysate (C12 peptide) reduces blood pressure in prehypertensive subjects, Am. J. Hypertens. 20 (2007) 1–5.

    Google Scholar 

  18. Cheung H.S., Cushman D.W., Inhibition of homogeneous angiotensin-converting enzyme of rabbit lung by synthetic venom peptides of Bothrops jararaca, Biochim. Biophys. Acta-Enzymol. 293 (1973) 451–463.

    CAS  Google Scholar 

  19. Christensen J.E., Dudley E.G., Pederson J.A., Steele J.L., Peptidases and amino acid catabolism in lactic acid bacteria, Antonie van Leeuwenhoek, Int. J. Gen. Molec. Microbiol. 76 (1999) 217–246.

    CAS  Google Scholar 

  20. Curtis J.M., Dennis D., Waddell D.S., MacGillivray T., Ewart H.S., Determination of angiotensin-converting enzyme inhibitory peptide Leu-Lys-Pro-Asn-Met (LKPNM) in bonito muscle hydrolysates by LC-MS/MS, J. Agric. Food Chem. 50 (2002) 3919–3925.

    CAS  Google Scholar 

  21. Cushman D.W., Cheung H.S., Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung, Biochem. Pharmacol. 20 (1970) 1637–1648.

    Google Scholar 

  22. Dent M.P., O’Hagan S., Braun W.H., Schaetti P., Marburger A., Vogel O., A 90-day subchronic toxicity study and reproductive toxicity studies on ACE-inhibiting lactotripeptide, Food Chem. Toxicol. 45 (2007) 1468–1477.

    CAS  Google Scholar 

  23. Engberink M.F., Schouten E.G., Kok F.J., van Mierlo L.A.J., Brouwer I.A., Geleijnse J.M., Lactotripeptides show no effect on human blood pressure. Results from a double-blind randomized controlled trial, Hypertension 51 (2008) 399–405.

    CAS  Google Scholar 

  24. FitzGerald R.J., Murray B.A., Bioactive peptides and lactic fermentations, Int. J. Dairy Technol. 59 (2006) 118–125.

    CAS  Google Scholar 

  25. FitzGerald R.J., Murray B.A., Walsh D.J., Hypotensive peptides from milk proteins, J. Nutr. 134 (2004) 980S-988S.

    CAS  Google Scholar 

  26. Foltz M., Meynen E.E., Bianco V., van Platerink C., Koning T.M.M.G., Kloek J., Angiotensin converting enzyme inhibitory peptides from a lactotripeptide-enriched milk beverage are absorbed intact into the circulation, J. Nutr. 137 (2007) 953–958.

    CAS  Google Scholar 

  27. Fuglsang A., Nilsson D., Nyborg N.C.B., Cardiovascular effects of fermented milk containing angiotensin-converting enzyme inhibitors evaluated in permanently catheterized, spontaneously hypertensive rats, Appl. Environ. Microbiol. 68 (2002) 3566–3569.

    CAS  Google Scholar 

  28. Gagnaire V., Mollé D., Herrouin M., Léonil J., Peptides identified during Emmental cheese ripening: origin and proteolytic systems involved, J. Agric. Food Chem. 49 (2001) 4402–4413.

    CAS  Google Scholar 

  29. Gavras H., Brunner H.R., Role of angiotensin and its inhibition in hypertension, ischemic heart disease, and heart failure, Hypertension 37 (2001) 342–345.

    CAS  Google Scholar 

  30. Gobbetti M., Ferranti P., Smacchi E., Goffredi F., Addeo F., Production of angiotensin-I-converting-enzyme-inhibitory peptides in fermented milks started by Lactobacillus delbrueckii subsp. bulgaricus SS1 and Lactococcus lactis subsp. cremoris FT4, Appl. Environ. Microbiol. 66 (2000) 3898–3904.

    CAS  Google Scholar 

  31. Gómez-Ruiz J.Á., Ramos M., Recio I., Angiotensin-converting enzyme-inhibitory peptides in Manchego cheeses manufactured with different starter cultures, Int. Dairy J. 12 (2002) 697–706.

    Google Scholar 

  32. Gómez-Ruiz J.Á., Ramos M., Recio I., Angiotensin converting enzyme-inhibitory activity of peptides isolated from Manchego cheese. Stability under simulated gastrointestinal digestion, Int. Dairy J. 14 (2004) 1075–1080.

    Google Scholar 

  33. Gómez-Ruiz J.Á., Ramos M., Recio I., Identification and formation of angiotensin-converting enzyme-inhibitory peptides in Manchego cheese by high-performance liquid chromatography-tandem mass spectrometry, J. Chromatogr. A 1054 (2004) 269–277.

    Google Scholar 

  34. Gómez-Ruiz J.Á., Taborda G., Amigo L., Ramos M., Molina E., Sensory and mass spectrometric analysis of the peptidic fraction lower than one thousand daltons in Manchego cheese, J. Dairy Sci. 90 (2007) 4966–4973.

    Google Scholar 

  35. Gómez-Ruiz J.Á., Taborda G., Amigo L., Recio I., Ramos M., Identification of ACE-inhibitory peptides in different Spanish cheeses by tandem mass spectrometry, Eur. Food Res. Technol. 223 (2006) 595–601.5.

    Google Scholar 

  36. Haque E., Chand R., Antihypertensive and antimicrobial bioactive peptides from milk proteins, Eur. Food Res. Technol. 227 (2008) 7–15.

    CAS  Google Scholar 

  37. Hata Y., Yamamoto M., Ohni M., Nakajima K., Nakamura Y., Takano T., A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects, Am. J. Clin. Nutr. 64 (1996) 767–771.

    CAS  Google Scholar 

  38. Hernández-Ledesma B., Amigo L., Ramos M., Recio I., Angiotensin converting enzyme inhibitory activity in commercial fermented products, Formation of peptides under simulated gastrointestinal digestion, J. Agric. Food Chem. 52 (2004) 1504–1510.

    Google Scholar 

  39. Inoue K., Shirai T., Ochiai H., Kasao M., Hayakawa K., Kimura M., Sansawa H., Blood-pressure-lowering effect of a novel fermented milk containing γ-aminobutyric acid (GABA) in mild hypertensives, Eur. J. Clin. Nutr. 57 (2003) 490–495.

    CAS  Google Scholar 

  40. Jang A., Lee M., Purification and identification of angiotensin converting enzyme inhibitory peptides from beef hydrolysates, Meat Sci. 69 (2005) 653–661.

    CAS  Google Scholar 

  41. Jauhiainen T., Blood pressure lowering effects of Lactobacillus helveticus fermented milk containing bioactive peptides Ile-Pro-Pro and Val-Pro-Pro: mechanistic, kinetic and clinical studies, Diss. University Helsinki, 2007, pp. 1–100.

  42. Jauhiainen T., Vapaatalo H., Poussa T., Kyrönpalo S., Rasmussen M., Korpela R., Lactobacillus helveticus fermented milk lowers blood pressure in hypertensive subjects in 24-h ambulatory blood pressure measurement, Am. J. Hypertens. 18 (2005) 1600–1605.

    Google Scholar 

  43. Jauhiainen T., Wuolle K., Vapaatalo H., Kerojoki O., Nurmela K., Lowrie C., Korpela R., Oral absorption, tissue distribution and excretion of a radiolabelled analog of a milk-derived antihypertensive peptide, Ile-Pro-Pro, in rats, Int. Dairy J. 17 (2007) 1216–1223.

    CAS  Google Scholar 

  44. Kajimoto O., Aihara K., Hirata H., Takahashi R., Nakamura Y., Safety evaluation of excessive intake of the tablet containing “Lactotripeptides (VPP, IPP)” on healthy volunteers, J. Nutr. Food 4 (2001) 37–46.

    Google Scholar 

  45. Kamath V., Niketh S., Chandrashekar A., Rajini P.S., Chymotryptic hydrolysates of α-kafirin, the storage protein of sorghum (Sorghum bicolor) exhibited angiotensin converting enzyme inhibitory activity, Food Chem. 100 (2007) 306–311.

    CAS  Google Scholar 

  46. Katayama K., Anggraeni H.E., Mori T., Ahhmed A.M., Kawahara S., Sugiyama M., Nakayama T., Maruyama M., Muguruma M., Porcine skeletal muscle troponin is a good source of peptides with angiotensin-I converting enzyme inhibitory activity and antihypertensive effects in spontaneously hypertensive rats, J. Agric. Food Chem. 56 (2008) 355–360.

    CAS  Google Scholar 

  47. Katayama K., Jamhari, Mori T., Kawahara S., Miake K., Kodama Y., Sugiyama M., Kawamura Y., Nakayama T., Maruyama M., Muguruma M., Angiotensin-I converting enzyme inhibitory peptide derived from porcine skeletal muscle myosin and its antihypertensive activity in spontaneously hypertensive rats, J. Food Sci. 72 (2007) S702-S706.

    CAS  Google Scholar 

  48. Kenny O., FitzGerald R.J., O’Cuinn G., Beresford T., Jordan K., Growth phase and growth medium effects on the peptidase activities of Lactobacillus helveticus, Int. Dairy J. 13 (2003) 509–516.

    CAS  Google Scholar 

  49. Kilpi E.E.R., Kahala M.M., Steele J.L., Pihlanto A.M., Joutsjoki V.V., Angiotensin I-converting enzyme inhibitory activity in milk fermented by wild-type and peptidase-deletion derivatives of Lactobacillus helveticus CNRZ32, Int. Dairy J. 17 (2007) 976–984.

    CAS  Google Scholar 

  50. Korhonen H., Milk-derived bioactive peptides: From science to applications, J. Funct. Foods 1 (2009) 177–187.

    CAS  Google Scholar 

  51. Kurosaki T., Maeno M., Mennear J.H., Bernard B.K., Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): VI. Effects of Lactobacillus helveticus-fermented milk powder on fertility and reproductive performance of rats, Int. J. Toxicol. 24 (2005) 61–89.

    CAS  Google Scholar 

  52. Leclerc P.L., Gauthier S.F., Bachelard H., Santure M., Roy D., Antihypertensive activity of casein-enriched milk fermented by Lactobacillus helveticus, Int. Dairy J. 12 (2002) 995–1004.

    CAS  Google Scholar 

  53. Li G.H., Le G.W., Shi Y.H., Shrestha S., Angiotensin I-converting enzyme inhibitory peptides derived from food proteins and their physiological and pharmacological effects, Nutr. Res. 24 (2004) 469–486.

    CAS  Google Scholar 

  54. Lo W.M.Y., Li-Chan E.C.Y., Angiotensin I converting enzyme inhibitory peptides from in vitro pepsin-pancreatin digestion of soy protein, J. Agric. Food Chem. 53 (2005) 3369–3376.

    CAS  Google Scholar 

  55. Maeno M., Mizuno S., Mennear J.H., Bernard B.K., Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): VIII. Assessment of cytotoxicity and clastogenicity of tripeptides-containing casein hydrolysate and Lactobacillus helv- eticus-fermented milk powders in Chinese hamster lung cells, Int. J. Toxicol. 24 (2005) 97–105.

    CAS  Google Scholar 

  56. Maeno M., Nakamura Y., Mennear J.H., Bernard B.K., Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): III. Single- and/or repeated-dose toxicity of tripeptides-containing Lactobacillus helveticus-fermented milk powder and casein hydrolysate in rats, Int. J. Toxicol. 24 (2005) 13–23.

    CAS  Google Scholar 

  57. Maeno M., Yamamoto N., Takano T., Identification of an antihypertensive peptide from casein hydrolysate produced by a proteinase from Lactobacillus helveticus CP790, J. Dairy Sci. 79 (1996) 1316–1321.

    CAS  Google Scholar 

  58. Mäkinen S., Kelloniemi J., Pihlanto A., Mäkinen K., Korhonen H., Hopia A., Valkonen J.P.T., Inhibition of angiotensin converting enzyme I caused by autolysis of potato proteins by enzymatic activities confined to different parts of the potato tuber, J. Agric. Food Chem. 56 (2008) 9875–9883.

    Google Scholar 

  59. Masuda O., Nakamura Y., Takano T., Antihypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats, J. Nutr. 126 (1996) 3063–3068.

    CAS  Google Scholar 

  60. Matsufuji H., Matsui T., Seki E., Osajima K., Nakashima M., Osajima Y., Angiotensin I-converting enzyme inhibitory peptides in an alkaline protease hydrolyzate derived from sardine muscle, Biosci. Biotechnol. Biochem. 58 (1994) 2244–2245.

    CAS  Google Scholar 

  61. Matsui T., Matsufuji H., Seki E., Osajima K., Nakashima M., Osajima Y., Inhibition of angiotensin I-converting enzyme by Bacillus licheniformis alkaline protease hydrolyzates derived from sardine muscle, Biosci. Biotechnol. Biochem. 57 (1993) 922–925.

    CAS  Google Scholar 

  62. Matsui T., Yukiyoshi A., Doi S., Sugimoto H., Yamada H., Matsumoto K., Gastrointestinal enzyme production of bioactive peptides from royal jelly protein, their antihypertensive ability in SHR, J. Nutr. Biochem. 13 (2002) 80–86.

    CAS  Google Scholar 

  63. McCarron D.A., Reusser M.E., Finding consensus in the dietary calcium-blood pressure debate, J. Am. Coll. Nutr. 18 (1999) 398S-405S.

    CAS  Google Scholar 

  64. Meisel H., Goepfert A., Günther S., ACE-inhibitory activities in milk products, Milchwissenschaft-Milk Sci. Int. 52 (1997) 307–311.

    CAS  Google Scholar 

  65. Meisel H., Walsh D.J., Murray B., Fitz-Gerald R.J., ACE inhibiting peptides, in: Mine Y., Shahidi S. (Eds.), Nutraceutical Proteins and Peptides in Health and Disease, CRC Press, New York, USA, 2006, pp. 269–315.

    Google Scholar 

  66. Meyer J., Bütikofer U., Walther B., Wechsler D., Sieber R., Changes in angiotensin-converting enzyme inhibition and concentrations of the tripeptides Val-Pro-Pro and Ile-Pro-Pro during ripening of different Swiss cheese varieties, J. Dairy Sci. 92 (2009) 826–836.

    CAS  Google Scholar 

  67. Miguel M., Aleixandre A., Antihypertensive peptides derived from egg proteins, J. Nutr. 136 (2006) 1457–1460.

    CAS  Google Scholar 

  68. Miguel M., Manso M., Aleixandre A., Alonso M.J., Salaices M., López-Fandiño R., Vascular effects, angiotensin I-converting enzyme (ACE)-inhibitory activity, and antihypertensive properties of peptides derived from egg white, J. Agric. Food Chem. 55 (2007) 10615–10621.

    CAS  Google Scholar 

  69. Minervini F., Algaron F., Rizzello C.G., Fox P.F., Monnet V., Gobbetti A., Angiotensin I-converting-enzyme-inhibitory and antibacterial peptides from Lactobacillus helveticus PR4 proteinase-hydrolyzed caseins of milk from six species, Appl. Environ. Microbiol. 69 (2003) 5297–5305.

    CAS  Google Scholar 

  70. Mito K., Fujii M., Kuwahara M., Matsumura N., Shimizu T., Sugano S., Karaki H., Antihypertensive effect of angiotensin I-converting enzyme inhibitory peptides derived from hemoglobin, Eur. J. Pharmacol. 304 (1996) 93–98.

    CAS  Google Scholar 

  71. Miyoshi S., Kaneko T., Yoshizawa Y., Fukui F., Tanaka H., Maruyama S., Hypotensive activity of enzymatic α-zein hydrolysate, Agric. Biol. Chem. 55 (1991) 1407–1408.

    CAS  Google Scholar 

  72. Mizuno S., Matsuura K., Gotou T., Nishimura S., Kajimoto O., Yabune M., Kajimoto Y., Yamamoto N., Antihypertensive effect of casein hydrolysate in a placebo-controlled study in subjects with high-normal blood pressure and mild hypertension, Br. J. Nutr. 94 (2005) 84–91.

    CAS  Google Scholar 

  73. Mizuno S., Mennear J.H., Matsuura K., Bernard B.K., Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline, L-isoleucyl-L-prolyl-L-proline): V. A 13-week toxicity study of tripeptides-containing casein hydrolysate in male and female rats, Int. J. Toxicol. 24 (2005) 41–59.

    CAS  Google Scholar 

  74. Mizushima S., Ohshige K., Watanabe J., Kimura M., Kadowaki T., Nakamura Y., Tochikubo O., Ueshima H., Randomized controlled trial of sour milk on blood pressure in borderline hypertensive men, Am. J. Hypertens. 17 (2004) 701–706.

    Google Scholar 

  75. Möller N.P., Scholz-Ahrens K.E., Roos N., Schrezenmeir J., Bioactive peptides and proteins from foods: indication for health effects, Eur. J. Nutr. 47 (2008) 171–182.

    Google Scholar 

  76. Muguerza B., Ramos M., Sanchez E., Manso M.A., Miguel M., Aleixandre A., Delgado M.A., Recio I., Antihypertensive activity of milk fermented by Enterococcus faecalis strains isolated from raw milk, Int. Dairy J. 16 (2006) 61–69.

    CAS  Google Scholar 

  77. Nakamura Y., Bando I., Mennear J.H., Bernard B.K., Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): IV. Assessment of the repeated-dose toxicological potential of synthesized L-valyl-L-prolyl-L-proline in male and female rats and dogs, Int. J. Toxicol. 24 (2005) 25–39.

    CAS  Google Scholar 

  78. Nakamura Y., Takano T., Angiotensin converting enzyme inhibitor and method for preparing same, US Patent 5449661, 1995.

  79. Nakamura Y., Yamamoto N., Sakai K., Okubo A., Yamazaki S., Takano T., Purification and characterization of angiotensin I-converting enzyme inhibitors from sour milk, J. Dairy Sci. 78 (1995) 777–783.

    CAS  Google Scholar 

  80. Nakamura Y., Yamamoto N., Sakai K., Takano T., Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme, J. Dairy Sci. 78 (1995) 1253–1257.

    CAS  Google Scholar 

  81. Nakano D., Ogura K., Miyakoshi M., Ishii F., Kawanishi H., Kurumazuka D., Kwak C.J., Ikemura K., Takaoka M., Moriguchi S., Iino T., Kusumoto A., Asami S., Shibata H., Kiso Y., Matsumura Y., Antihyperten-sive effect of angiotensin I-converting enzyme inhibitory peptides from a sesame protein hydrolysate in spontaneously hypertensive rats, Biosci. Biotechnol. Biochem. 70 (2006) 1118–1126.

    CAS  Google Scholar 

  82. Nielsen M.S., Martinussen T., Flambard B., Sørensen K.I., Otte J., Peptide profiles and angiotensin-I-converting enzyme inhibitory activity of fermented milk products: effect of bacterial strain, fermentation pH, and storage time, Int. Dairy J. 19 (2009) 155–165.

    CAS  Google Scholar 

  83. Nussberger J., Blutdrucksenkende Tripeptide aus der Milch, Ther. Umsch. 64 (2007) 177–179.

    CAS  Google Scholar 

  84. Ohsawa K., Satsu H., Ohki K., Enjoh M., Takano T., Shimizu M., Producibility and digestibility of antihypertensive β-casein tripeptides, Val-Pro-Pro and Ile-Pro-Pro, in the gastrointestinal tract: analyses using an in vitro model of mammalian gastrointestinal digestion, J. Agric. Food Chem. 56 (2008) 854–858.

    CAS  Google Scholar 

  85. Okamoto A., Hanagata H., Matsumoto E., Kawamura Y., Koizumi Y., Yanagida F., Angiotensin-converting enzyme inhibitory activities of various fermented foods, Biosci. Biotechnol. Biochem. 59 (1995) 1147–1149.

    CAS  Google Scholar 

  86. Ong L., Henriksson A., Shah N.P., Angiotensin converting enzyme-inhibitory activity in Cheddar cheeses made with the addition of probiotic Lactobacillus casei sp., Lait 87 (2007) 149–165.

    CAS  Google Scholar 

  87. Ong L., Shah N.P., Influence of probiotic Lactobacillus acidophilus and L. helveticus on proteolysis, organic acid profiles, and ACE-inhibitory activity of Cheddar cheeses ripened at 4, 8, and 12 °C, J. Food Sci. 73 (2008) M111-M120.

    CAS  Google Scholar 

  88. Ong L., Shah N.P., Release and identification of angiotensin-converting enzyme-inhibitory peptides as influenced by ripening temperatures and probiotic adjuncts in Cheddar cheeses, LWT — Food Sci. Technol. 41 (2008) 1555–1566.

    CAS  Google Scholar 

  89. Pan D., Luo Y., Tanokura M., Antihypertensive peptides from skimmed milk hydrolysate digested by cell-free extract of Lactobacillus helveticus JCM1004, Food Chem. 91 (2005) 123–129.

    CAS  Google Scholar 

  90. Parrot S., Degraeve P., Curia C., Martial-Gros A., In vitro study on digestion of peptides in Emmental cheese: analytical evaluation and influence on angiotensin I converting enzyme inhibitory peptides, Nahrung-Food 47 (2003) 87–94.

    CAS  Google Scholar 

  91. Pihlanto A., Akkanen S., Korhonen H.J., ACE-inhibitory and antioxidant properties of potato (Solanum tuberosum), Food Chem. 109 (2008) 104–112.

    CAS  Google Scholar 

  92. Ponstein-Simarro Doorten A.Y., vdWiel J.A.G., Jonker D., Safety evaluation of an IPP tripeptide-containing milk protein hydrolysate, Food Chem. Toxicol. 47 (2009) 55–61.

    Google Scholar 

  93. Pozo-Bayón M.A., Alcaide J.M., Polo M.C., Pueyo E., Angiotensin I-converting enzyme inhibitory compounds in white and red wines, Food Chem. 100 (2007) 43–47.

    Google Scholar 

  94. Pripp A.H., Effect of peptides derived from food proteins on blood pressure: a meta-analysis of randomized controlled trials, Food Nutr. Res. 52 (2008) DOI: 10.3402/fnr.v52i0.1641. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596738/pdf/FNR-52-1641.pdf.

  95. Pripp A.H., Sørensen R., Stepaniak L., Sørhaug T., Relationship between proteolysis and angiotensin-I-converting enzyme inhibition in different cheeses, LWT — Food Sci. Technol. 39 (2006) 677–683.

    CAS  Google Scholar 

  96. Prospective Studies Collaboration, Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies, Lancet 360 (2002) 1903–1913.

    Google Scholar 

  97. Quirós A., Chichón R., Recio I., López-Fandiño R., The use of high hydrostatic pressure to promote the proteolysis and release of bioactive peptides from ovalbumin, Food Chem. 104 (2007) 1734–1739.

    Google Scholar 

  98. Quist E.E., Phillips R.D., Saalia F.K., Angiotensin converting enzyme inhibitory activity of proteolytic digests of peanut (Arachis hypogaea L.) flour, LWT — Food Sci. Technol. 42 (2009) 694–699.

    CAS  Google Scholar 

  99. Rank T.C., Grappin R., Olson N.F., Secondary proteolysis of cheese during ripening. A review, J. Dairy Sci. 68 (1985) 801–805.

    CAS  Google Scholar 

  100. Robert M.C., Razaname A., Mutter M., Juillerat M.A., Identification of angiotensin-I-converting enzyme inhibitory peptides derived from sodium caseinate hydrolysates produced by Lactobacillus helveticus NCC 2765, J. Agric. Food Chem. 52 (2004) 6923–6931.

    CAS  Google Scholar 

  101. Rufián-Henares J.A., Morales F.J., Angiotensin-I converting enzyme inhibitory activity of coffee melanoidins, J. Agric. Food Chem. 55 (2007) 1480–1485.

    Google Scholar 

  102. Ryhänen E.L., Pihlanto-Leppälä A., Pahkala E., A new type of ripened, low-fat cheese with bioactive properties, Int. Dairy J. 11 (2001) 441–447.

    Google Scholar 

  103. Saiga A., Iwai K., Hayakawa T., Takahata Y., Kitamura S., Nishimura T., Morimatsu F., Angiotensin I-converting enzyme-inhibitory peptides obtained from chicken collagen hydrolysate, J. Agric. Food Chem. 56 (2008) 9586–9591.

    CAS  Google Scholar 

  104. Saiga A., Okumura T., Makihara T., Katsuda S.I., Morimatsu F., Nishimura T., Action mechanism of an angiotensin I-converting enzyme inhibitory peptide derived from chicken breast muscle, J. Agric. Food Chem. 54 (2006) 942–945.

    CAS  Google Scholar 

  105. Saito T., Nakamura T., Kitazawa H., Kawai Y., Itoh T., Isolation and structural analysis of antihypertensive peptides that exist naturally in Gouda cheese, J. Dairy Sci. 83 (2000) 1434–1440.

    CAS  Google Scholar 

  106. Sano J., Ohki K., Higuchi T., Aihara K., Mizuno S., Kajimoto O., Nakagawa S., Kajimoto Y., Nakamura Y., Safety evaluation of excessive intake of drink containing “lactotripeptides (VPP, IPP)” in subjects with normal blood pressure to mild hypertension, J. Nutr. Food 7 (2005) 17–30.

    Google Scholar 

  107. Savijoki K., Palva A., Purification and molecular characterization of a tripeptidase (PepT) from Lactobacillus helveticus, Appl. Environ. Microbiol. 66 (2000) 794–800.

    CAS  Google Scholar 

  108. Schär H., Glättli H., Moor U., Nick B., Sieber R., Steiger G., Untersuchungen über den Reifungsverlauf von qualitativ gutem Walliser Raclettekäse, Schweiz. Milchwirt. Forsch. 21 (1992) 52–57.

    Google Scholar 

  109. Seppo L., Jauhiainen T., Poussa T., Korpela R., A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects, Am. J. Clin. Nutr. 77 (2003) 326–330.

    CAS  Google Scholar 

  110. Seppo L., Kerojoki O., Suomalainen T., Korpela R., The effect of a Lactobacillus helveticus LBK-16 H fermented milk on hypertension — a pilot study on humans, Milchwissenschaft-Milk Sci. Int. 57 (2002) 124–127.

    CAS  Google Scholar 

  111. Shalaby S.M., Zakora M., Otte J., Performance of two commonly used angiotensin-converting enzyme inhibition assays using FA-PGG and HHL as substrates, J. Dairy Res. 73 (2006) 178–186.

    CAS  Google Scholar 

  112. Sheih I.-C., Fang T.J., Wu T.-K., Isolation and characterisation of a novel angiotensin I-converting enzyme (ACE) inhibitory peptide from the algae protein waste, Food Chem. 115 (2009) 279–284.

    CAS  Google Scholar 

  113. Shuangquan, Tsuda H., Myamoto T., Angiotensin I-converting enzyme inhibitory peptides in skim milk fermented with Lactobacillus helveticus 130B4 from camel milk in Inner Mongolia, China, J. Sci. Food Agric. 88 (2008) 2688–2692.

    CAS  Google Scholar 

  114. Sieber R., Käse — ein wertvolles Lebensmittel in der menschlichen Ernährung, Mitt. Lebensm. Hyg. 96 (2005) 141–170.

    CAS  Google Scholar 

  115. Silva S.V., Pihlanto A., Malcata F.X., Bioactive peptides in ovine and caprine cheeselike systems prepared with proteases from Cynara cardunculus, J. Dairy Sci. 89 (2006) 3336–3344.

    CAS  Google Scholar 

  116. Sipola M., Finckenberg P., Korpela R., Vapaatalo H., Nurminen M.L., Effect of long-term intake of milk products on blood pressure in hypertensive rats, J. Dairy Res. 69 (2002) 103–111.

    CAS  Google Scholar 

  117. Sipola M., Finckenberg P., Santisteban J., Korpela R., Vapaatalo H., Nurminen M.L., Long-term intake of milk peptides attenuates development of hypertension in spontaneously hypertensive rats, J. Physiol. Pharmacol. 52 (2001) 745–754.

    CAS  Google Scholar 

  118. Smacchi E., Gobbetti M., Peptides from several Italian cheeses inhibitory to proteolytic enzymes of lactic acid bacteria, Pseudomonas fluorescens ATCC 948 and to the angiotensin I-converting enzyme, Enzyme Microb. Technol. 22 (1998) 687–694.

    CAS  Google Scholar 

  119. Sollberger H., Glättli H., Nick B., Rüegg M., Sieber R., Steiger G., Untersuchungen über den Reifungsverlauf guter Sbrinz-Käse, Schweiz. Milchwirt. Forschung 20 (1991) 63–69.

    Google Scholar 

  120. Steffen C., Rentsch F., Nick B., Steiger G., Sieber R., Glättli H., Eberhard P., Reifungsverlauf in qualitativ gutem Gruyère, Landwirt. Schweiz 5 (1992) 209–215.

    Google Scholar 

  121. Steffen C., Schär H., Eberhard P., Glättli H., Nick B., Rentsch F., Steiger G., Sieber R., Untersuchungen über den Reifungsverlauf von qualitativ gutem Käse: Appenzeller, Schweiz. Milchwirt. Forsch. 21 (1993) 39–45.

    Google Scholar 

  122. Steffen C., Schär H., Eberhard P., Glättli H., Nick B., Rentsch F., Steiger G., Sieber R., Untersuchungen über den Reifungsverlauf von qualitativ gutem Käse: Tilsiter aus Rohmilch, Schweiz. Milchwirt. Forsch. 21 (1993) 46–51.

    Google Scholar 

  123. Stepaniak L., Jedrychowski L., Wróblewska B., Sørhaug T., Immunoreactivity and inhibition of angiotensin-I converting enzyme and lactococcal oligopeptidase by peptides from cheese, Ital. J. Food Sci. 13 (2001) 373–381.

    CAS  Google Scholar 

  124. Taubert D., Roesen R., Schömig E., Effect of cocoa and tea intake on blood pressure. A meta-analysis, Arch. Int. Med. 167 (2007) 626–634.

    CAS  Google Scholar 

  125. Tonouchi H., Suzuki M., Uchida M., Oda M., Antihypertensive effect of an angiotensin converting enzyme inhibitory peptide from enzyme modified cheese, J. Dairy Res. 75 (2008) 284–290.

    CAS  Google Scholar 

  126. Tossavainen O., Suomalainen T., Sahlstein J., Mäyrä-Mäkinen A., Verfahren zur Herstellung eines Produktes, welches gegen Bluthochdruck gerichtete Tripeptide enthält, Dt. Patent DE 600 10 742 T2 (2005).

  127. Townsend R.R., McFadden C.B., Ford V., Cadée J.A., A randomized, double-blind, placebo-controlled trial of casein protein hydrolysate (C12 peptide) in human essential hypertension, Am. J. Hypertens. 17 (2004) 1056–1058.

    CAS  Google Scholar 

  128. Tuomilehto J., Lindström J., Hyyrynen J., Korpela R., Karhunen M.L., Mikkola L., Jauhiainen T., Seppo L., Nissinen A., Effect of ingesting sour milk fermented using Lactobacillus helveticus bacteria producing tripeptides on blood pressure in subjects with mild hypertension, J. Hum. Hypertens. 18 (2004) 795–802.

    CAS  Google Scholar 

  129. van der Pijl P.C., Kies A.K., Ten Have G.A.M., Duchateau G.S.M.J.E., Deutz N.E.P., Pharmacokinetics of proline-rich tripeptides in the pig, Peptides 29 (2008) 2196–2202.

    Google Scholar 

  130. van der Zander K., Bots M.L., Bak A.A.A., Koning M.M.G., de Leeuw P.W., Enzymatically hydrolyzed lactotripeptides do not lower blood pressure in mildly hypertensive subjects, Am. J. Clin. Nutr. 88 (2008) 1697–1702.

    Google Scholar 

  131. van Mierlo L.A.J., Koning M.M.G., van der Zander K., Draijer R., Lactotripeptides do not lower ambulatory blood pressure in untreated whites: results from 2 controlled multicenter crossover studies, Am. J. Clin. Nutr. 89 (2009) 617–623.

    Google Scholar 

  132. van Platerink C.J., Janssen H.G., Horsten R., Haverkamp J., Quantification of ACE inhibiting peptides in human plasma using high performance liquid chromatographymass spectrometry, J. Chromatogr. B 830 (2006) 151–157.

    Google Scholar 

  133. Vermeirssen V., Van Camp J., Verstraete W., Optimisation and validation of an angiotensin-converting enzyme inhibition assay for the screening of bioactive peptides, J. Biochem. Biophys. Methods 51 (2002) 75–87.

    CAS  Google Scholar 

  134. Wang J., Hu J., Cui J., Bai X., Du Y., Miyaguchi Y., Lin B., Purification and identification of a ACE inhibitory peptide from oyster proteins hydrolysate and the antihypertensive effect of hydrolysate in spontaneously hypertensive rats, Food Chem. 111 (2008) 302–308.

    CAS  Google Scholar 

  135. Webb A.J., Patel N., Loukogeorgakis S., Okorie M., Aboud Z., Misra S., Rashid R., Miall P., Deanfield J., Benjamin N., MacAllister R., Hobbs A.J., Ahluwalia A., Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite, Hypertension 51 (2008) 784–790.

    CAS  Google Scholar 

  136. Xu J.Y., Qin L.Q., Wang P.Y., Li W., Chang C., Effect of milk tripeptides on blood pressure: a meta-analysis of randomized controlled trials, Nutrition 24 (2008) 933–940.

    CAS  Google Scholar 

  137. Yamamoto N., Akino A., Takano T., Antihypertensive effect of the peptides derived from casein by an extracellular proteinase from Lactobacillus helveticus CP790, J. Dairy Sci. 77 (1994) 917–922.

    CAS  Google Scholar 

  138. Yamamoto N., Akino A., Takano T., Antihypertensive effects of different kinds of fermented milk in spontaneously hypertensive rats, Biosci. Biotechnol. Biochem. 58 (1994) 776–778.

    CAS  Google Scholar 

  139. Yamamoto N., Maeno M., Takano T., Purification and characterization of an antihypertensive peptide from a yogurt-like product fermented by Lactobacillus helveticus CPN4, J. Dairy Sci. 82 (1999) 1388–1393.

    CAS  Google Scholar 

  140. Yang Y., Tao G., Liu P., Liu J., Peptide with angiotensin I-converting enzyme inhibitory activity from hydrolyzed corn gluten meal, J. Agric. Food Chem. 55 (2007) 7891–7895.

    CAS  Google Scholar 

  141. Yano S., Suzuki K., Funatsu G., Isolation from α-zein of thermolysin peptides with angiotensin I-converting enzyme inhibitory activity, Biosci. Biotechnol. Biochem. 60 (1996) 661–663.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Agroscope Liebefeld-Posieux Research Station ALP, 3003, Berne, Switzerland

    Robert Sieber, Ueli Bütikofer, Charlotte Egger, Reto Portmann, Barbara Walther & Daniel Wechsler

Authors
  1. Robert Sieber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ueli Bütikofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charlotte Egger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reto Portmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barbara Walther
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel Wechsler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel Wechsler.

About this article

Cite this article

Sieber, R., Bütikofer, U., Egger, C. et al. ACE-inhibitory activity and ACE-inhibiting peptides in different cheese varieties. Dairy Sci. Technol. 90, 47–73 (2010). https://doi.org/10.1051/dst/2009049

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1051/dst/2009049

Search

Navigation