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The main approach used in vitro for antihypertensive food-derived peptides is the angiotensin I-converting enzyme (ACE) to determine the IC50 as an expression of the peptide effectiveness. ACE is a dipeptidyl carboxypeptidase (EC., originally isolated from horse blood (25), andcatalyzes the conversion of angiotensin I (decapeptide) to angiotensin II (octapeptide) by removing the C-terminal dipeptide His–Leu. Angiotensin II is a potent vasoconstrictor that increases peripheral vascular resistance and consequently elevates arterial pressure (41).

Angiotensin I-converting enzyme mechanisms. ACE also catalyzes the degradation of bradykinin, which is a known vasodilator (48). Inhibition of ACE activity leads to a decrease in the concentration of angiotensin II and increases the level of bradykinin, resulting in diminished blood pressure (41). The influences of ACE on blood pressure have made it an ideal target for the treatment of hypertension. To date, abundant ACE-inhibitory peptides have been identified from hydrolytic products of food proteins (20, 49-56). The inhibitory activities and sequences of some of these peptides are remarkably different. Because the primary activity of ACE is to cleave the C-terminal dipeptide of oligopeptide substrates with a wide specificity, the inhibitory activity of ACE-inhibitory peptides is strongly influenced by their C-terminal tripeptide sequence. The most potent ACE inhibitors contain hydrophobic amino acid residues at each of the three C-terminal positions that interact with the subsites S1, S19, and S29 at the ACE active site. Many studies have shown that peptides with high ACE-inhibitory activities have tryptophan, phenylalanine, tyrosine, or proline at their C-terminus and branched aliphatic amino acids at the N-terminus, and ACE is known to have little affinity for inhibitors with C-terminal dicarboxylic amino acids, such as Glu (50). Also, the crystallography structures of ACE and complexes of ACE with inhibitors have been demonstrated that the inhibition mechanism of ACE is based on a competitive inhibition mechanism in which inhibitors occupy the active site of ACE and compete with substrate HHL to bind in the active site.

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            In addition to the competitive inhibition mechanism, many ACE-inhibitory peptides follow non-competitive inhibition mechanism. The non-competitive inhibitory peptides have been found in foods such as chickpeas, sardines, oysters, and tuna. Also, a highly active ACE-inhibitory hexapeptide has been purified from yeast with amino acid sequence Thr-Pro-Thr-Gln-Gln-Ser (TPTQQS), but the peptide does not have the characteristics of the highly active ACE-inhibitory peptides (42, 57, 58, 59). Thus, the peptide can combine with the ACE molecule and act as a non-competitive inhibitor to produce a dead-end complex, irrespective of whether a substrate molecule is bound or not. The complex between ACE and TPTQQS can prevent the formation of the reaction product, HA. Pre-forming of docking simulation (docking of TPTQQS onto ACE) revealed that the peptide TPTQQS, by forming coordination bonds with the zinc in the active site, and the H-bonds with other amino acids outside of the active site, played a key role in providing the inhibitory effect of TPTQQS (60).

            Renin angiotensin system. The renin angiotensin system (RAS) pathway is another target for the treatment of hypertension, it is inhibited at three possible levels: ACE, upstream renin activity, or downstream angiotensin type 1 (AT1) receptors, which are the common mechanisms used in designing antihypertensive drugs (56, 61). Angiotensin II specifically has a prothrombotic potential effect which enhances adhesion and aggregation of platelets, leading to vasoconstriction and increased blood pressure, or hypertension (61).

The kallikrein–kinin system represents a metabolic cascade that triggers the release of vasoactive kinins, among which the vasodilatory nonapeptide bradykinin is best known (62). The RAS and kallikrein–kinin systems are connected by ACE, which degrades angiotensin I (Ang I) and bradykinin. The endothelin system (ET) system is another peptidic system and has an important role in blood pressure regulation (58). The production of endothelin from a precursor polypeptide, preproendothelin (preproET-1), which is consecutively cleaved to generate the active form, ET-1, is a strong vasoconstrictor and pressor (59).  

RAS versus nitric oxide system in ACE inhibition. ACE inhibition is largely related to two types of blood pressure systems, the RAS (renin–angiotensin system) and NOS (nitric oxide system). As for the mechanism of hypertension, the N-terminus of the prohormone angiotensinogen, derived from the liver, is released by the enzyme renin, generating the decapeptide angiotensin ? (Ang ?). Ang 1 is converted to Ang II which decreases blood pressure by action of ACE. Therefore, ACE inhibitors can exert antihypertensive effects by decreasing the formation of Ang II and the degradation of bradykinin (Fig. 1). Moreover, Ang II binds to AT1 and AT2 receptor, especially AT1 receptor, inducing production of 90 vasoconstriction. As mentioned above, ACE inactivates the bradykinin which binds to ?-receptors that cause an increase in intracellular Ca2+ level. The increased Ca2+ level and bradykinin cause nitric oxide synthase to convert L-arginine to nitric oxide, which is a strong vasodilator. Therefore, it is assumed that the main regulations of blood pressure by peptides could be related with RAS and NOS pathway. Antihypertensive mechanisms can be exerted through the promotion of bradykinin activity, inhibition of the release of endothelin-1 by endothelial cells, induction of endothelium-derived nitric oxide production (eNOS), reduction of the expression of vascular cell adhesion molecule-1 (VCAM-1), and transforming growth factor beta (TGF-?) genes, suggesting that these inhibitors exert a preventive effect on the functions and binding of mononuclear cells to arterial cells (63). 

Recently, milk peptides have been investigated for lipid-lowering and antithrombotic capabilities. A proposed mechanism of milk derived bioactive peptides pertains to the interaction with endothelial cells and monocytes during the initial phases of atheroschlerosis. Antilipaemic-specific capabilities are also possible from whey protein and other globulin-derived peptides. Lactostatin is an effective cholesterol-lowering peptide that interacts with extracellular kinases that influence calcium concentrations within the MAPK signaling pathway, along with expression of the CYP7A1 gene that increases cholesterol catabolism (64). At high hydrostatic pressure (HHP) and flavurzyme hydrolysis, casein hydrolysate demonstrated its ability to suppress nitric oxide (NO) production and synthesis of pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW 264.7 macrophage cells (65).



Hydrophobicity effects on peptide inhibition of ACE

Moskowitz proposed a model that explains the clinical superiority of hydrophobic-based ACE inhibition in comparison with that of hydrophilic (66). By binding to different sites of the enzyme molecule, hydrophobic peptides can inhibit ACE by blocking the catalytic site at N-terminal residues, resulting inspecific local benefits, such as decreased systemic blood pressure (67). In this case, the blood pressure decrease caused by a hydrophobic amino acid can be presumed to be due to ACE competitive inhibition fromthe strong binding effect of hydrophobic interaction between the enzyme and the ligand (68). In addition, the interactions between ACE inhibitors and Zn2+ at the enzyme site, which are known to hydrophobic and H-bond interactions, are responsible for modulating catalysis (69).

Interactions in biological system –  in vivo mechanisms. Antihypertensive peptides are one of the most studied food-protein compounds, due to the prevalence of hypertension as a serious health problem among broad cardiovascular diseases. Hypertension is defined as containing an elevated blood pressure of 140/90 mmHg or above (4, 71). Because hypertension can increase the risk of coronary heart, peripheral artery disease, stroke, and kidney disease, any reduction in its associated biological activity or health impact can be favorable (35).

The biochemical pathway of antihypertensive bioactive peptides involves interactions with carbohydrates at the cellular level, in relation to impacting blood glucose levels. The management benefits of antihypertensive peptides on blood pressure and angiotensin-converting enzyme have been well documented, and it is revealed that those angiotensin-converting enzyme inhibitors might play a beneficial effect on plasma glucose (52). In vivo experiments on ‘spontaneously-hypertensive’ rats showed that the soy peptide fractions had significantly dropped blood pressure when they were administered orally. These experiments also showed that alcalase digests of soy protein also produced antihypertensive peptides (24). When oral doses of these peptides were given in a dose-dependent manner, there was a significant (P<0.05) reduction in systolic blood pressure in the rats. However, higher doses (1000 mg/kg of body 21 weight/day) did not show any effect on the blood pressure of normotensive rats. Evidence showed that the incidence of diabetes was reduced by 20% in patients treated with captopril, in comparison to other treatments (57). It is suggested that angiotensin-converting enzyme inhibitors are less likely to impair glucose metabolism than other antihypertensive treatments (59, 72. However, hypertension is often an insulin-resistant state and is a condition that often affects people with Type 2 diabetes (48), but it is still not clear whether their angiotensin-converting enzyme inhibitors play a protective effect role on diabetes compare with other classes of medication agents.


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