Effects of milk casein-derived tripeptides Ile-Pro-Pro, Val-Pro-Pro, and Leu-Pro-Pro on enzymes processing vasoactive precursors in vitro

 

 Buy Article Permissions and Reprints

Abstract

Milk-based drinks containing casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown topossess antihypertensive and vascularendothelium-protecting properties in hy-pertensive animal models. Furthermorein clinical intervention trials they reduceblood pressure and arterial stiffness. Theexact mechanisms are not known, but inhibition of angiotensin converting enzyme 1 (ACE1) has been suggested mainlyto mediate these beneficial effects

The present study investigated the in vitro effects of three tripeptides: Ile-Pro-Pro, Val-Pro-Pro and leucine-proline-proline (Leu-Pro-Pro) on four reninangiotensin system enzymes: ACE1ACE2, chymase, and cathepsin G. Also their effects on arginase I, a critical enzyme in L-arginine-nitric oxide pathway were studied

It was shown, apparently for the firsttime, that the inhibitory effects of Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro on ACE1 at micromolar concentrations arecompetitive in nature. Therefore the efficacy of inhibition is largely dependent onthe amount of substrate present. Inhibition of ACE2 and arginase I was reachedonly at concentrations three orders of magnitude greater. No inhibition of chymase and cathepsin G was observed by the tripeptides

The findings support the hypothesis that Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro act favourably on blood pressure mainly by selective inhibition of ACE1.

• Literatur

• 1 McCarron DA, Morris CD, Henry HJ, Stanton JL. Bloodpressure and nutrient intake in the United States. Science. 1984; 224: 1392-8
  CrossrefPubMedGoogle Scholar
• 2 Burke V, Hodgson JM, Beilin LJ, Giangiulioi N, Rogers P, Puddey IB. Dietary protein and soluble fibre reduce ambulatory blood pressure in treated hypertensives. Hypertension. 2001; 38: 821-6
  CrossrefPubMedGoogle Scholar
• 3 Xu JY, Qin LQ, Wang PY, Li W, Chang C. Effect of milk tripeptides on blood pressure: a meta-analysis of randomizedcontrolled trials. Nutrition. 2008; 24: 933-40
  CrossrefPubMedGoogle Scholar
• 4 FitzGerald RJ, Murray BA, Walsh DJ. Hypotensive peptidefrom milk proteins. J Nutr. 2004; 134: 980S-8S
  PubMedGoogle Scholar
• 5 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. 1995; 78: 777-83
  CrossrefPubMedGoogle Scholar
• 6 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. 1996; 126: 3063-8
  PubMedGoogle Scholar
• 7 Sipola M, Finckenberg P, Korpela R, Vapaatalo H, Nurminen ML. Effect of long term intake of milk products on blood pressure in hypertensive rats. J Dairy Res. 2002; 69: 103-11
  PubMedGoogle Scholar
• 8 Jauhiainen T, Collin M, Narva M, Cheng ZJ, Poussa T, Vapaatalo H et al Effect of long-term intake of milk peptides and minerals on blood pressure and arterial function in spontaneously hypertensive rats. Milk Sci Int. 2005; 60: 358-63
  PubMedGoogle Scholar
• 9 Jauhiainen T, Vapaatalo H, Poussa T, Kyrönpalo S, Rasmussen M, Korpela R. Lactobacillus helveticus-fermented milk lowers blood pressure in hypertensive subjects in 24-hambulatory blood pressure measurement. Am J Hypertens. 2005; 18: 1600-5
  CrossrefPubMedGoogle Scholar
• 10 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. 2003; 77: 326-30
  PubMedGoogle Scholar
• 11 Jauhiainen T, Vapaatalo H, Poussa T, Kyrönpalo S, Rasmussen H, Korpela R. Lactobacillus helveticus-fermented milk reduces arterial stiffness in hypertensive subjects. Int Dairy J. 2007; 17: 1209-11
  CrossrefPubMedGoogle Scholar
• 12 Jäkälä P, Jauhiainen T, Korpela R, Vapaatalo H. Bioactive tripeptides Ile-Pro-Pro and Val-Pro-Pro protect endothelial function in vitro in normotensive rats. Basic Clin Pharmacol Toxicol. 2008; 102 (1) 51-2
  PubMedGoogle Scholar
• 13 Demougeot C, Prigent-Tessier A, Marie C, Berthelot A. Arginase inhibition reduces endothelial dysfunction and blood pressure rising in spontaneously hypertensive rats. J Hypertens. 2005; 23: 933-4
  CrossrefPubMedGoogle Scholar
• 14 Huynh NN, Chin-Dusting J. Amino acids, arginase and nitric oxide in vascular health. Clin Exp Pharmacol Physiol. 2006; 33: 1-8
  CrossrefPubMedGoogle Scholar
• 15 Carvajal N, Cederbaum SD. Kinetics of inhibition of rat liver and kidney arginases by proline and branched-chainamino acids. Biochim Biophys Acta. 1986; 870: 181-4
  CrossrefPubMedGoogle Scholar
• 16 Cushman DW, Cheung HS. Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbitlung. Biochem Pharmacol. 1971; 20: 1637-4
  CrossrefPubMedGoogle Scholar
• 17 Jauhiainen T, Wuolle K, Vapaatalo H, Kerojoki O, Nurmela K, Lowrie C et al Oral absorption, tissue distribution and excretion of a radiolabelled analog of a milk-derived antihy-pertensive peptide, Ile-Pro-Pro, in rats. Int Dairy J. 2007; 17: 1216-23
  CrossrefPubMedGoogle Scholar
• 18 Luhtala S, Vaajanen A, Oksala O, Valjakka J, Vapaatalo H. Activities of angiotensin-converting enzymes ACE1 and ACE2, and inhibition by bioactive peptides in porcine ocular tissues. J Ocul Pharmacol Ther. 2009; 25: 23-8
  CrossrefPubMedGoogle Scholar