Open access peer-reviewed chapter
Abstract
Today hypertension has become a threat to the human lives. Different factors like sensitivity to sodium, obesity, alcohol consumption, sedentary lifestyle and smoking are responsible for the development of hypertension. Hypertension can be of major risk factor to cardiovascular diseases (CVD). Because of their small molecular mass, bioactive peptides have an important role in the digestion and absorption of proteins. Angiotensin converting enzyme inhibitory (ACE-I) peptides are one of the most widely used bioactive peptide in the field of medicine and food processing. Thus, these inhibitors are applied to regulate the blood pressure and prevent hypertension. Synthetic ACE inhibitors have various side effects and that is why scientists nowadays, are focusing on the natural alternate of ACE inhibitors with promising health properties. Two types of proteins found in milk are casein and whey proteins which are a good source of the bioactive peptides having a positive impact on body functions. ACE inhibitory peptides derived from the goat milk proteins are considered to be used in nutraceuticals and pharmaceutical products to reduce the hypertension ultimately reducing the risk of CVD and other related diseases.
Keywords
- Hypertension
- Bioactive peptides
- Goat milk
- ACE-I peptides
- Health benefits
1. Introduction
1.1 Hypertension
Up to 30% of the adult population in most of the countries, hypertension is considered as a major risk factor for cardiovascular disease [1]. In the human body the regulation of BP is done by cardiac output and peripheral resistance. Heart rate and stroke volume are the two factors which adjusts the cardiac output, while the changes in the smooth muscles in arteries and arterioles adjusts the peripheral resistance [2].
Hypertension can be categorized as primary hypertension and secondary hypertension. Primary hypertension is mainly found in the adults, it can develop over years and do not possesses distinct identifiable cause so it is named as primary hypertension. Various underlying causes or effects of certain medication leads to the development of hypertension, that is secondary hypertension [3].
Although no distinct cause is found for primary hypertension, but there are many factors which are responsible for setting of primary hypertension. The factors which leads to the development of primary hypertension are: obesity, sodium sensitivity, smoking, extreme consumption of alcohol, sedentary lifestyles. All these factors are supposed to be associated with the chronic elevation of BP in primary hypertension [4].
Hypertension is observed as distinct disease and can be regarded as major risk factor to the CVD; it contributes directly to the renal failure, peripheral arterial disease, stroke, artery disease and congestive heart failure. If successful BP reduction is achieved then the risk of CVD and incidence of coronary mortality particularly with the elderly having multiple risk factors, can be dramatically reduced. In the later age that is older than 60 or also in the middle ages BP leads to the incidence of CVD. As the age increases the BP lowering drugs becomes most prescribed drugs for older than 60. Among all the CVD risk factors, hypertension is the most common risk factor for CVD [3].
Some factors are considered important in the development of hypertension. These factors include variation in genetic makeup, aging, style of living, overweight and nutrition. Diseases like Pheochromocytoma, Diabetes, Cushing syndrome, Kidney disease, Congenital adrenal hyperplasia are also involved in creating hypertension. Along with the factors mentioned above, some medications like hormone therapy for menopause, oral contraceptives, and excessive intake of alcohol are contributor in developing hypertension [5].
A number of pathophysiological factors have been involved in the genesis of essential hypertension which includes increase in the sympathetic nervous system activity possibly related to increase exposure to psychological stress. Other factors involved in the genesis of hypertension includes inadequate intake of potassium and calcium, increase in the production of sodium retaining hormones and vasoconstrictors, long term intake of sodium intake, increases or inappropriate secretion of enzyme renin which results in the increase production of Ang II and aldosterone [6].
1.2 ACE inhibitors
Recently, bioactive peptides have become an interesting research topic in the field of food and medicine. Due to the small molecular mass of these peptides, they allow easy digestion and absorption of proteins by the human body. These biological active peptides are involved in the regulation of physiological functions of the body, help in the development and growth for humans by providing nutrition, and play an important role in prevention and treatment of diseases [7].
As a functional ingredient, bioactive peptides with hypertensive activities can be used in food to deliver to consumers [8]. Within the proteins structure, the bioactive peptides are inactive, different methods are used to release them [9].
In humans, ACE act as a metalloproteinase with zinc catalytic active sites, resulting in raising the blood pressure by converting angiotensin to angiotensin-II. Thus, ACE inhibitors are applied in the regulation of the blood pressure for the protection of the organ targeted [10].
2. Mechanism of action of ACE inhibitors
As far as mechanism of ACE is concerned, inactive decapeptide is converted into potent vasopressor octapeptide AngII by the action of ACE enzymes which also inactivates the formation of bradykinin [11]. Currently the focus of research is the study of the underlying processes related to ACE inhibition. ACE enzyme is zinc protease which plays essential role in the regulation of BP because it is responsible for the conversion of Ang I to Ang II. As a result of this C-terminal dipeptide and aldosterone is released which leads to the constriction of blood vessels as result the BP rises Furthermore, sodium ions also accumulates in the human body and cause rise in in the SBP [12, 13]. In addition, bradykinin which is a potent vasodilator is also hydrolyzed by the action of ACE which becomes responsible for further increase in BP, so, the inhibition of this ACE is supposed to lower the BP [14].
3. Angiotensin II blockage
Renin is an enzyme produced in the juxtramedullary cells of the kidney and secreted in blood circulation. Renin converts its substrate angiotensinogen into Ang I. The zinc metallo peptidase Ang I is converted ino Ang II when His-Leu is removed from Ang I by the action of the ACE. This Ang II is very potent vasoconstrictor and endorses the sodium retention by rising tubular reabsorption of sodium (Figure 1).
Figure 1.
Effect of Ang II blockage on BP reduction.
The presence of RAAS tissues is detected in various tissues of the human body. The organs of the human body where the presence of ACE is detected includes brain, heart, kidney and vessels, the angiotensin in these tissues expresses in two ways either locally or enter in the circulation. ACE inhibitors causes in the reduction of BP by decreasing the local Ang II devoid of the ACE in plasma [15]. Conversion of Ang I into Ang II is blocked by ACE-I and also the cleavage of bradykinin to inactive metabolites is prevented. ACE enzyme also cleave other peptides, but the majority of pharmacological properties of inhibitors can be credited to decrease of Ang II and maintenance of bradykinin [16]. In humans, ACE inhibitors lower BP in all forms of hypertension. ACE inhibitors are generally effective across all age classes, but show greater probability of efficacy in white rather than black patients. After prolonged dosing ACE maintain their effectiveness, even though Ang II levels in plasma may return to pretreatment levels [17]. This phenomenon, termed “angiotensin escape,” may be the result of Ang II formation by enzymes other than ACE, or by increased transcription of ACE [16].
3.1 Bradykinin potentiating
The pharmacological effect of bradykinin potentiation activity first shed light on the therapeutic potential of ACE inhibition because it occurs in parallel with RAAS blockade after administration of ACE inhibitors (Figure 2).
Figure 2.
ACE-I lowers the incidence of hypertension by vasodilation, while formation of inactive fragments raises the BP by vasoconstriction. PVR; peripheral vascular resistance.
Kininogen is precursor of bradykinin. The two enzymes, plasma and tissue kallikrein acts on kininogen and convert it into bradykinin. The hormone acts through the B2 receptor present in the endothelial cells and are responsible for the release of vasodilator substances such as nitric oxide and prostaglandin I2. Pharmacological blockade of this receptor has been shown to blunt the antihypertensive properties of ACE-I [18]. While reduced renal kallikrein activity may be associated with hypertension, a causal relationship between this phenomenon and elevated blood pressure has not been established. Therefore, while bradykinin may contribute to the antihypertensive pharmacology of ACE-Is, the significance of the kallikein-kinin pathway in cardiovascular disease is outdone by the many actions attributable to angiotensin II.
4. Pharmacological approach
Frequently, synthetic inhibitors are used to minimize the extremity of hypertension. These include enalapril, lisinopril, ramipril, fosinopril, captopril but these have some side effects. Therefore, exploring the ACE inhibitors from natural sources with health promoting qualities is the need of hour [5, 19].
5. Non-pharmacological approach
Non-pharmacological approaches include alternate to pharmacological approach. This includes life style modifications. In the prevention and management of CVD, diet plays a vital role. Intake of low fat containing dairy product, maximum usage of vegetables, and maximum intake of fruits is suggested to reduce sodium intake so that hypertension can be controlled. If required, weight drop and exercise is also suggested [3].
5.1 Natural alternate
The famous Dietary Approaches to Stop Hypertension (DASH) diet decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 5.5 and 3.0 mmHg, respectively [20]. Diet containing fruits and vegetables alone caused BP reduction roughly half of the DASH diet, which in addition to fruits and vegetables also contain low-fat dairy products [21].
However, the greater reduction in SBP cannot be ascribed to milk products only because other dietary alteration e.g. reduced saturated fat was also incorporated into DASH diet. Nonetheless, the relationship between the intake of milk products and reduction in BP is demonstrated by many other intervention studies [22].
As an alternative to ACE-I synthetic drugs, for their ability to reduce toxic effects of chemically synthesized drugs in humans and prevention of hypertension, ACE-I peptides from natural sources like food proteins have attracted great attention [8].
Other than source of essential amino acids, proteins from milk also are a great source of the bioactive peptides having various benefits of health. The benefits of peptides derived from the milk protein include antioxidant effects, activities of immunomodulators, ACE-I and antihypertensive effects [9].
6. Methodology
A study conducted in 2016 by Bao et al. compared four types of commercial proteases. These included neutral protease, alcalase, flavourozyme and proteinase K because of their higher ACE inhibitory activity in skimmed goat and cow milk. Alcalase and proteinase K showed much higher degree of hydrolysis (DH) than neutral protease and flavourozyme for both skimmed goat and cow milk. The results showed that ACE inhibitory peptides from goat milk produced by alcalase was the best having ACE inhibitory activity of 95.31%. While ACE inhibitory peptides from the hydrolysis of cow milk by proteinase K, showed 81.28% ACE inhibitory activity [23].
In the year 2017, the experimentation of Ibrahim et al. on the digestion of isolated whey and casein proteins of goat milk by the gastric pepsin paved the way as a candidate for antihypertensive bioactive peptides. The gastric pepsin produced soluble hydrolysates which exhibited the inhibition of ACE. The fractionation of hydrolysates was carried out into four fractions (F1 ~ F4) by size exclusion chromatography, Sephacryl S-100 column. Peptides in both whey and casein F4 fractions were isolated by RP-HPLC. The hydrophobic peptide peaks showed the most potent inhibitor of ACE. The results from this experiment, for the first time, introduced new potent ACE inhibitory peptides which can be derived from the goat milk whey and casein and are released by gastric pepsin [19].
Another study was conducted by Tagliazucchi et al. which involved a newly developed harmonized static in vitro digestion model, with mass spectrometry (MS) for the identification of bioactive peptides. The main objective of the study was the identification of ACE inhibitory peptides from the skimmed goat milk which are released after the gastro-intestinal digestion. By using ultrafiltration peptides were extracted from the post pancreatic digest and by RP-HPLC followed by MS these peptides were isolated. The sequences which were identified, there were 18 identical to bioactive peptides with ACE inhibitory activities. During in vitro gastro intestinal digestion of goat milk protein, the antihypertensive tripeptides VPP and IPP were released. Thus, to study the release of short bioactive peptides during gastro intestinal transport, the research outlines the appropriateness of the harmonized digestive model system [24].
In 2018, a study conducted by the Shu et al. the hydrolysis of cow and goat milk were performed by four commercial proteases which include trypsin, papain, alkaline protease and bromelain. The comparison between the ACE inhibitory activity of cow and goat milk was measured. The hydrolysates which were treated by alkaline protease showed the highest degree of hydrolysis DH. Moreover, the ACE inhibitory activity of the hydrolysates derived from goat milk was higher than that of hydrolysates derived from cow milk. Therefore, a proper enzyme is required for the development of functional milk products like ACE inhibitory peptides [7].
In another study, Chen et al. used a novel wild strain
Experiment conducted by Parmar and fellows showed that the goat milk fermented with
The research of Aslam et al. showed the hydrolysis of goat milk protein with
Last year, the research of Parmar et al. reported the study of five different cultures of
| Methodology | Technique | Enzyme | Peptide Sequence | References |
|---|---|---|---|---|
| Ultrafiltration size exclusion chromatography SDS-PAGE Q executive Hybrid Quadrapole-Orbitrap Mass Spectrometry | VLPVPQKAVPQ VLPVPQKVVPQ TQTPVVVPPFLQPEIMGVPKVKE | [5] | ||
| Fermentation by | Response surface methodology (RSM) ultrafiltration gel chromatography RP- HPLC | [1] | ||
| Enzymatic hydrolysis | Alcalase, flavourzyme, neutral protease proteinase K | [23] | ||
| Enzymatic Hydrolysis | Centrifugation Spectrophotometry | Alkaline protease trypsin bromelain papain | HHL | [7] |
| Enzymatic Hydrolysis | MALDI-TOF MS RP-HPLC | Pepsin | HHL | [19] |
| Enzymatic Hydrolysis | Centrifugation UV/Visible Spectrophotometry | Protease Trypsin Pepsin papain | HHL | [8] |
7. Milk and BP
Milk is a fluid that is secreted from the female mammary glands of mammalian species, and its primitive function is to meet the complete nutritional requirements of infants. Proteins present in milk consists of 80% caseins and 20% whey proteins [27].
Milk is rich in calcium, potassium and magnesium. A number of studies have showed the importance of calcium and its effect on BP. A meta-analysis of 40 studies, which includes 2492 subjects showed that the calcium supplementation decreased SBP and DBP by 1.9 mmHg and 10 mmHg respectively [28].
7.1 Molecular properties of milk proteins
Various systems of proteins are synthesized through the formation of monomer subunit associations. Those associations have a fixed structure, and they contain several identical or different subunits or many identical subunits. Casein and whey proteins make up the protein system of milk. Whey protein molecules comprises of globular structure with a relatively high content of helical structures and a balanced distribution of acidic and basic amino acid residues and hydrophobic and hydrophilic amino acid residues along the polypeptide chain [29]. In contrast to standard globular proteins such as whey proteins, casein is characterized by a unique, amphiphilic structure.
Proteins from the milk are a precursor of different biologically active peptides, but many peptides in milk are inactive, therefore, require hydrolysis for their release [7, 30].
One of the good source of the bioactive peptides which have a positive impact on body functions is from the caseins and whey proteins of the milk. The release of these inactive peptides present within the precursor protein sequence is done by the enzymatic hydrolysis or by fermenting with lactic acid bacteria, in vivo or in vitro. Other methods which include DNA recombinant technology, chemical synthesis and extraction from the natural foods have also been confirmed for releasing bioactive peptides [7].
In a nine year’s follow up study of 6912 white, non-hypertensive men and women showed that the subjects consuming less than one serving of low- fat milk per day have risk of getting hypertension while those subjects consuming low-fat milk per day had lower increase of high BP. Similarly, a potential study of 3,157 young adults having age between 18 and 30 years surveyed for 10 years found that the frequency of elevated BP was inversely associated with total intake of dairy products, if subjects had body mass index (BMI) ≥ 25 but not in normal weight subjects [31, 32].
8. Goat milk
Because of the presence of all the essential amino acids without a high concentration of fats and mucus producing substances, goat milk is considered to be a perfect food [27]. Because utilization of bovine milk has become the cause of food allergy in infants, the importance of goat milk is constantly increasing. Therefore, when there is a shortage of human milk, goat milk proteins are highly recommended because of their property of being more digestible [19].
Goat milk is different from cow or human milk in capacity of buffer, alkalinity, and digestibility but have various health benefits. In the maintenance of health and nutrition of young and elderly, goat milk has played an important role [25]. The amino acid composition of goat milk protein is closer to that of human breast milk than to bovine or caprine milk [1].
All over the world, the production and consumption of goat milk and dairy products is increasing. Goat milk has a unique advantage to other milk. The immunoglobulins are more abundant in goat milk than breast milk [33] Also, the amount of proteins, fats, minerals, vitamins, and other nutrients of goat milk are much higher than other milk [10]. In the production of ACE-I peptides after fermentation, goat milk is considered a better choice among other dairy species [5].
8.1 ACE-I peptides from goat milk
In processed dairy products (cheese, milk etc.) antihypertensive peptides have been found without any intended functional role. Valine-Proline-Proline (Val-Pro-Pro) and lactotripeptides Isoleucine-Proline-Proline (Ile-Pro-Pro) have been obtained from sour milk. Although casein and whey have shown effect in decreasing the BP but nowadays research is focused on their degradation products called as peptides [24, 34, 35].
Different studies reported that ACE-inhibitory peptides can come from different sources like animal products, marine organisms, and plants. And are derived by hydrolyzing enzymes such as pepsin, chymotrypsin, and trypsin and microbial enzymes such as alcalase, thermolysin, flavourzyme, and proteinase K [36].
Some findings reinforced the possible beneficial effects by consuming fermented goat milk. It helps in the prevention of cardiovascular diseases in association with oxidative stress and hypertension [37].
For the development of products of pharmaceuticals and nutraceuticals, bioactive peptides derived from the milk proteins are considered. As a suitable source for the generation of bio-functional ingredients to prevent and treat hypertension, a study provided a theoretical base for the development of goat milk derived proteins [27].
Among the sequences identified after the in vitro gastro intestinal digestion of skimmed goat milk, 18 were the bioactive peptides with ACE-I activity [24].
Fermented goat milk produced by
8.2 Biochemical aspects of milk derived ACE-I peptides
As far as the biochemical aspects of milk derived ACE-I peptides are concerned, the endothelial ACE contains two homologous domains which are named as N-terminal and C-terminal, both domains are catalytically active, ACE domain bind to any of the domain or may prefer to both. However, C-terminal is dominant angiotensin converting site as well as it seems necessary for BP regulation. The molecular mass of majority of ACE-I peptides is low while they possess short chain. These are consistent with the findings of Aslam [5].
Although ACE-inhibitory effect of a hypotensive peptide could be verified
ACE activity of the N-terminal domain. It was determined that neither plasma nor endothelial ACE was inhibited and no specific effect was observed on N-terminal or C-terminal ACE-domains [38].
The structure–activity relationships have indicated that the most promising tripeptide structure possess hydrophobic amino acid in the N-terminal, aromatic amino acid at the C-terminal and positively charged at the middle position. As far as the ACE-I dipeptides are concerned, the presence of amino acid residue with large side chain as well as hydrophobic side chain is preferred. The presence of amino acids Asp, Gly and Pro at N-terminal as well as Pro-Ser-Thr at the C-terminal are responsible for the stability of peptide towards luminal enzymatic peptide hydrolysis. In the analysis of peptide stability and permeability it was observed that many dipeptides such as Ile-Pro-Pro exhibited high ACE-I activity
8.3 Safety aspects of goat milk derived ACE-I peptide
The milk of cow which is an essential part of human nutrition holds a safe reputation. Peptide sequences of different length are generated when the ingested milk in the gastrointestinal tract is attacked by different enzymes which hydrolyze the milk protein. The human body is constantly exposed to the protein hydrolyzates without facing side effects. Moreover, Food Drug Authority have listed the hydrolyzates obtained from the protein as “generally recognized as safe” (GRAS). However, European countries have issued no health claim regarding the protein hydrolyzates and also not authorized the milk protein derived peptides as GRAS. Drugs acting as ACE-inhibitors, such as captopril and enalapril, hold some common adverse effects, which could theoretically concern also milk-derived antihypertensive peptides because of their ACE-I activity. ACE-inhibitors control RAAS and cough, hypotension and hyperkalemia are the most commonly reported adverse effects. However, dozens of clinical studies with different kinds of antihypertensive peptide products have been executed and no treatment-related safety concerns have appeared [46, 47].
Casein hydrolyzates as well as Val-Pro-Pro have showed no toxicity when toxicological studies were carried out on animals. There was no indication to support establishment of either the Lowest Observed Effect Level or Maximally Tolerated Dose; both being greater than 2 g/kg/day. Similarly, no adverse effects associated to casein-derived tripeptides were observed in a subchronic (90-day) repeated-dose toxicity study with rats or in a pre-natal growth study with rabbits [48].
The tripeptide generated by hydrolyzing the milk protein with enzyme preparation derived from
8.4 Application prospects of goat milk derived ACE inhibitory peptides
The peptides possess multifunctional properties and are easily absorbed. Therefore, ACE-I peptides derived from food sources hold a great promise in the development of a novel physiological functional food peptides foe preventing high BP as well as for therapeutic purposes. Moreover, these peptides can serve as starting compounds for the development of antihypertensive drugs against ACE. In Japan, soup containing ACE-I peptides and as well as sour milk have been marketed to cure hypertension. In Japan, the thermolysin digest of dried bonito (called “Katsuobushi oligopeptide”) has been officially approved as Foods for Specified Health Use by the Ministry of Health and Welfare in Japan [50, 51].
It should be noted, however, that the physiological activity of many bioactive milk components has been analyzed mostly in
Therefore, this matter requires high interest and importance to reveal whether these ACE-I peptides also possess the effects that of commonly used synthetic drugs. In spite of the results obtained from these antihypertensive peptides from food proteins, it should also be considered that these results are obtained from
The concentration of future research should be on the content, biologically availability of peptides, and milk derivatives in protein. Future studies to understand and investigate the physiological mechanism responsible for the bioactivity of these peptides could be possible only with the applications of proteomic, metabolomics method and peptidomic. The process of enriching foods with peptides can also give rise to legal concerns when health claims are made on the resulting end products [52].
9. Bioavailability
Generally, after oral dosing the peptides are rapidly metabolized to the constituent amino acids by the peptidases present at the brush border membrane and the bioavailability and absorption remains very low. However, it is reported that at least dipeptide and tripeptides are absorbed intact, which later on enter in the circulation and produce systemic effects. The absorption of bioactive peptides is carried out via carrier-mediated transport or paracellular diffusion. Apparently, short tripeptides are actively transported
Half-lives of absorption and elimination of ACE-I peptides are only few minutes. The resistance against many human proteolytic enzymes have been observed with ACE-I peptides possessing Pro or Pro-Pro residues at the C-terminal position [34, 43, 44]. Therefore, there is a strong likelihood that these peptides reach the circulation and target sites intact and exert also systemic effects. As concern the casein-derived radiolabelled tripeptide Ile-Pro-Pro, it was observed that it absorbed partly intact from the intestinal tract after a single dose to rats. Substantial amount of radioactively labeled peptides were detected from several tissues including liver, kidney and aorta. The process of excretion of the tripeptide was very slow, even after the 48 h the radiolabelled peptide was not completely excreted. Ile-Pro-Pro did not bind to albumin or other plasma proteins
10. Conclusion
Hypertension is observed as distinct disease and can be regarded as major risk factor to the CVD; it contributes directly to the renal failure, peripheral arterial disease, stroke, artery disease and congestive heart failure. If successful BP reduction is achieved then the risk of CVD and incidence of coronary mortality particularly with the elderly having multiple risk factors, can be dramatically reduced. Bioactive peptides which have a positive impact on body functions can be obtained from the caseins and whey proteins of the goat milk. The release of these inactive peptides present within the precursor protein sequence is done by the enzymatic hydrolysis or by fermenting with lactic acid bacteria, in vivo or in vitro. The research on antihypertensive bioactive peptides derived from natural the proteins of goat milk specially ACE-I peptides have shown significance over synthetic inhibitors for the treatment of hypertension. Therefore, the goat milk proteins have laid the foundation for an alternate natural source with lesser side effects and higher ACE-I activity. Thus, these bioactive peptides can be applied in the nutraceutical and pharmaceutical industries.
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