Effects of Milk Casein Derived Tripeptides on Endothelial Enzymes In Vitro; a Study with Synthetic Tripeptides

Abstract

In the fermentation of milk by certain lactic acid bacteria, casein is degraded into bioactive tripeptides shown to lower blood pressure in experimental animal models and in mildly hypertensive humans. This effect is suggested to result mainly in inhibition of angiotensin converting enzyme 1 (ACE-1). Due to the complexity of renin-angiotensin system (RAS), several other enzymes than ACE-1 can participate in the production of vasoactive components. Therefore, in the present study we investigated effects of tripeptides isoleucine-proline-proline (IPP), valine-proline-proline (VPP) and leucine-proline-proline (LPP) on some endothelial enzymes that are important in RAS or otherwise have a role in the endothelial function. The enzymes investigated were renin, chymase, neutral endopeptidase (NEP), prolyl oligopeptidase (POP), cathepsin G, endothelin converting enzyme 1 (ECE-1), and cyclooxygenase 1 and 2 (COX -1 and COX-2). The tripeptides inhibited prolyl oligopeptidase (POP) dose-dependently. IPP was the most potent inhibitor (IC50 486?95??M). Contrary, cathepsin G was activated by IPP, VPP and LPP as well as the amino acids proline and isoleucine. The other investigated enzymes were not affected. Inhibition of POP and activation of cathepsin G do not explain the blood pressure lowering effects of the tripeptides. Thus the inhibition of ACE-1 remains the most plausible mechanism of the antihypertensive effects of the tripeptides.

Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells

“…On the other hand, glioblastoma stem cells do not harbor CatG allowing a limited set of MHC I molecules on the cell surface to escape NK cell recognition. Cathepsin inhibitors or activators, for instance, lactoferrin, which is a natural CatG activator as published by us just recently, 175 or bioactive tripeptides, which increase CatG activity, 176 might reduce high cathepsin activity found in glioblastoma stem cells or reinstall such cathepsins necessary for supportive immune recognition. …”

Lactotripeptides Inhibiting ACE1 Elevate the Plasma Bradykinin Concentration Acutely in a Placebo-Controlled, Double-Blind, Cross-Over, 4-Week Trial in Healthy Volunteers

“…The antihypertensive mechanism of the lactotripeptides seems to be mediated mainly via ACE-1 inhibition and the reduced formation of the strongly vasoconstricting peptide, angiotensin II [4] [5] [24] [25] [26], even though other enzymes acting on the vasculature are also inhibited by these peptides [27].…”

Can Inhibitors of Snake Venom Phospholipases A2 Lead to New Insights into Anti-Inflammatory Therapy in Humans? A Theoretical Study

“…Among the various classes of existing PLA 2 , the human secreted PLA 2 of the IIA group (HGIIA) belongs to the group of PLA 2 that is the most associated with diseases and consequently are the target enzyme for inhibition [ 11 ]. Since human enzymes are difficult to obtain, some experimental models are generally employed for their study [ 12 , 13 , 14 , 15 , 16 ]. In this line, some enzymes that would possibly serve as an experimental model are the snake venoms PLA 2 ( sv PLA 2 ).…”