FI121058B - New use of therapeutically useful peptides - Google Patents

Description

Novel use of therapeutically useful peptides

Field of the Invention

The present invention relates to the prevention and treatment of endothelial dysfunction using biologically active peptides and products containing them. A product having a high concentration of short chain peptides has been found to be particularly effective for use according to the present invention.

The product for use in accordance with the present invention may be formulated, for example, as a health and well-being food or pharmaceutical product. It contains small molecule peptides, such as tripep-10 tides Ile-Pro-Pro (IPP), Val-Pro-Pro (VPP), or mixtures or concentrates containing them, and serves to improve epithelial function and treat related disorders. A particular aspect of the present invention is to reduce the stiffness of blood vessels and thereby increase their elasticity with small molecule peptides such as triple peptides Ile-Pro-Pro (IPP), Val-Pro-Pro (VPP), or mixtures thereof, concentrates or other products containing them.

Background of the Invention

Vascular endothelium locally regulates vascular tone by releasing vasodilators such as endothelial-derived relaxin-releasing factor (EDRF), nitric oxide, prostacyclin and endothelial-hyperpolarizing factor (EDHF), and vasoconstrictors such as and endothelin. The importance of nitric oxide in both basal and stimulated regulation of vascular tone and coronary microcirculation in large epicardial coronary arteries has been demonstrated in several clinical studies (see Vapaatalo H., Mervaala E., Clinically important factors in influencing endothelial function, Med Sci Monit 2001; 7 ( 5): 1075-1085; Drexler H., Hornig B., Endothelial dysfunction: a novel therapeutic target; J Mol Cell Cardiol 1999; 31: 51-60). The various endothelial-derived relaxing factors mentioned above repair endothelial dysfunction, for example in athero-30 sclerosis. The regulation of vasomotor tone, the modulation of blood coagulation, the promotion and prevention of vascular growth, the modulation of inflammation and the action of drugs and side effects are related to the endothelium. EDRF release is stimulated, for example, by increased release of bradykinin, thrombin, acetylcholine and serotonin.

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The endothelium regulates the tone of the underlying smooth muscle tissue in response to certain pharmacological and physiological stimuli. Endothelial function also contributes to vascular growth, leukocyte adhesion and immunological regulation, circulatory amine metabolism, lipoprotein metabolism and integration and transduction of blood-mediated signals.

Endothelial dysfunction is characterized by decreased secretion of vasodilatory neurotransmitters, increased production of vasoconstrictors, increased sensitivity to vasoconstrictors and / or resistance of vascular smooth muscle tissue to endothelial vasodilators. The dysfunction is the result of an imbalance between relaxing and reducing factors, or growth promoting and preventing agents. Inflammation, oxidation of lipoproteins, or other oxidative stress reactions are factors that influence the development and maintenance of endothelial dysfunction. Theoretically, the clearest and most direct indicators of endothelial dysfunction are nitric oxide and its metabolites, and cyclic GMP.

Endothelial dysfunction can be the cause or consequence of several clinical conditions such as hypertension, atherosclerosis, heart disease, heart failure, diabetes and high blood cholesterol. The most direct indicators of endothelial dysfunction are imbalances between vasodilatory factors such as nitric oxide, prostacyclin, endothelial-derived hyperpolarizing factor (EDHF), and natriuretic peptide production or receptor function, or endothelin: and thromboxane A2, increased formation or sensitivity to them.

Endothelial dysfunction can be treated with a number of known drugs, the most important of which are angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, nitrate products and cholesterol lowering drugs. The potency of ACE inhibitors is primarily based on their ability to enhance the effect of bradykinin, which promotes nitric oxide synthesis in the endothelium. In-30 induced and / or increased nitric oxide production or added nitrates may offset inadequate internal nitric oxide production. Drugs and nitrates act as exogenous EDRF and dilate blood vessels, and additionally act as an antithrombotic composition in damaged vessels.

WO 02/34767 A1, Selwood et al., Discloses Peptide-35 fragments of the vascular endothelial growth factor (VEGF) and useful in inhibiting angiogenesis. According to the invention, the peptides comprise three to eight amino acids, and one of the main features of the amino acid sequence is the presence and order of basic residues, in particular arginine residues (Arg) and / or lysine residues (Lys). Several peptides consisting of six to sixteen amino acids are specifically mentioned in the publication. None of these contains the sequences isoleucine-proline-proline (IPP) or valine-proline-proline (VPP). According to the publication, peptides may be useful in diseases in which angiogenesis plays a major role in the pathology. Such diseases may include, for example, diabetic retinopathy, age-related macular degeneration (ARDS), cancer, endometriosis, psoriasis and rheumatoid arthritis.

WO 99/45941 to Sandberg et al. Discloses a composition used to improve the softness, elasticity or appearance of a tissue. The composition is composed of peptides corresponding to any of the 41 peptide fragments formed by elastin thermolysis digestion. Preferably, the composition comprises a polypeptide of formula R 1 -valyl-valyl-prolyl-glutamine-R 2, wherein R 1 is the amino portion of the peptide and R 2 is the carboxy portion of the peptide. Preferably, the composition is applied to human skin in the form of a cosmetic agent. According to the disclosure, the composition may also be useful in the treatment of hypertension, coronary artery disease, arteriosclerosis, angina pectoris, coronary thrombosis, obstructive pulmonary disease, and restenosis following angioplasty.

WO 01/91700 A2 and U.S. Patent 6,962,904 B1, both to Mills et al., Are based in part on the same study as WO 99/45941, Sandberg et al. The publications describe compositions for increasing tissue elasticity, and the compositions are formed from peptides corresponding to the sequences present in the elastic, in particular, -valine-valine-proline and valine-valine-proline-asparagine. Said compositions are useful for improving elastin production in tissues. According to the publications, the main use here is also in cosmetics, but it is also mentioned that the compositions may be useful in the treatment of hypertension, coronary artery disease, hardening of the artery, angina pectoris, coronary artery thrombosis, obstructive pulmonary disease and restenosis after angioplasty.

The elastin peptide fragments described contain high levels of glycine and / or pro-moiety compared to other amino acid sequences. The fragments do not contain the sequences isoleucine-proline-proline (IPP) and / or valine-proline-proline (VPP).

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The preparation of bioactive peptides by fermentation has been extensively studied and described in the prior art in which milk-derived peptides are of particular interest. These have been shown to have, for example, opioid receptor binding properties, ACE inhibitory activity, and antimicrobial properties. For example, several studies have been conducted on hypertension, but the effects of peptides on endothelial function have not been described. In particular, the effects of the tripeptides valine-proline-proline (VPP) and isoleucine-proline-proline (IPP) and products containing them on endothelial functions have not been described in the prior art.

The tripeptides VPP and IPP are known compositions described as ACE inhibitors with antihypertensive activity. For example, in J Dairy Sci 78 (1995) 777-783 Nakamura et al. describe the use of an acid containing Lactobacillus helveticus and Saccharomyces cerevisiae for the preparation of two ACE inhibitors. Both compositions were identified as tripeptides, Val-Pro-Pro and Ile-Pro-Pro. Although the publication does not describe the in vivo antihypertensive effect of tripeptides, this is mentioned as the next subject of the study.

U.S. Patent No. 5,449,661 to Nakamura et al. Discloses the preparation of a peptide containing the tripeptide sequence Val-Pro-Pro and its use for lowering hypertension. The peptide is prepared by fermentation of skimmed milk powder with Lactobacillus helveticus strain JCM-1004, after which the peptide is purified by chromatography and freeze-dried.

In WO 99/16862 Yamamoto et al. describe Lactobacillus helveticus strain CM4, FERM BP-6060, which is capable of producing a large amount of tripeptides Val-Pro-Pro and / or Ile-Pro-Pro.

WO 01/32905, Valio, describes a product having antihypertensive properties and its preparation. The product is prepared by fermenting a casein-containing feedstock with a lactic acid bacterium and performing a nanofiltration of the resulting peptide-containing fermentation product. The antihypertensive properties of 30 are due in part to its tripeptide IPP and VPP. WO 03/070267, Valio, discloses the use of IPP and VPP and the product described in WO 01/32905 in the preparation of a mineral availability enhancing product. The product may be used, for example, to increase bone formation, strengthen bone, and treat or prevent osteoporosis.

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Blood vessels have effects in diseases related to viscoelasticity, including hypertension, arteriosclerosis, angina pectoris, angiogenesis, myocardial infarction, coronary artery thrombosis, post-angioplasty restenosis, and obstructive pulmonary disease.

5 Cardiovascular disease is the most common disease in the world and is one of the five fatal diseases in many countries. Unfortunately, rising living standards also increase the risk of these diseases, making them more important in the future. In addition to traditional medicines, there are now active products that offer consumers 10 interesting options.

Therefore, functional products that improve vascular elasticity and improve and normalize endothelial function would therefore be most welcome as part of a regular diet. In addition, it is also worth considering peptides having beneficial properties related to arterial stiffness as a medical or pharmaceutical product.

Brief Description of the Invention

It is therefore an object of the present invention to provide a product which, as part of a normal diet or as a medical and pharmaceutical product, improves or normalizes endothelial function and is thus capable of preventing, ameliorating or treating disorders and diseases associated with endothelial dysfunction. Endothelial dysfunction plays a significant role in vascular stiffness or flexibility, which in turn is a major contributor to several serious disorders including coronary artery disease, arteriosclerosis, angina pectoris, coronary artery thrombosis, obstructive pulmonary angiopathy. Thus, a particularly important feature of the present invention is the ability to increase vascular elasticity.

The product used according to the invention consists of or comprises endothelial enhancing peptides.

It is a further object of the present invention to provide a product either for use as such, for use as an endothelial enhancer, or for use in the manufacture of food or medicaments for the purpose of ingesting health.

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It is another object of the present invention to provide a preparation for the prevention, amelioration or treatment of endothelial dysfunction and related disorders and diseases comprising peptides that enhance endothelial function.

It is a further object of the present invention to provide a product for the prevention, amelioration or treatment of endothelial dysfunction and related disorders and diseases, which has a high content of casein-based, small-molecule peptides and is prepared by fermenting a casein-containing feedstock Lactobacillus helvetic strain LBK-16H, DSM 13137 or Lactobacillus helveticus strain LB 1936, DSM 17754, and optionally by partially or completely removing casein and / or other milk proteins and / or lactose in an amount sufficient to produce the desired effect. In a preferred embodiment, the fermented product is also nanofiltered.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, it has surprisingly been found that the above objects are achieved by using small molecule peptides, in particular triple peptides Ile-Pro-Pro (IPP), Val-Pro-pro (VPP). Said peptides have now been shown to be able to normalize endothelial function, improve vascular elasticity and prevent arterial stiffness.

The peptides used in accordance with the present invention are bioactive peptides corresponding to peptides obtained by hydrolysis of casein or casein-containing material such as milk. Short chain di-, tri- and tetrapeptides and mixtures thereof are considered suitable. In particular, the peptides are tripeptides IPP and VPP, mixtures of peptides containing IPP and VPP and products and compositions containing them.

The preferred embodiment provides excellent opportunities for the normalization of endothelial dysfunction and endothelium-dependent lesions.

The invention thus relates to the use of casein-based small molecule peptides in the manufacture of an endothelial enhancing product.

The invention further relates to the use of a product comprising casein-based small molecule peptides in the manufacture of an endothelial enhancing product.

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Preferably, the casein-based, small molecule peptides comprise di-, tri- and tetrapeptides and mixtures thereof. Most preferably, the IPP and VPP contents are high.

The invention further relates to the use of a product with a high content of casein-based small molecule peptides produced by fermentation of a casein-containing feedstock with a lactic acid bacterium and possibly by a nano-filtration of a fermented peptide-containing product in the preparation of an endothelial enhancing product.

In a preferred embodiment, the invention relates to the use of an acidified composition containing casein-derived peptides, minerals and live lactic acid bacteria in the manufacture of a product for improving endothelial dysfunction.

The invention also relates to a preparation for the normalization of endothelial function and endothelial dependent lesions comprising peptides which normalize endothelial function and endothelial dependent lesions.

The individual is above all a human individual. The positive effects of the products used in accordance with the invention are naturally also beneficial to animals, especially pets and farm animals. Examples include dogs, cats, rabbits, horses, cows, pigs, goats, sheep and poultry. The tripeptides VPP and IPP can be prepared synthetically or by hydrolysis of material containing said sequences. In a preferred embodiment, the peptides are prepared from casein or casein-containing starting material by fermentation. It is particularly preferred to use the method described in WO 01/32905, wherein the product containing the biologically active peptides is formed by fermentation followed by concentration and nano-filtration. This preferred embodiment provides excellent opportunities for using different types of starting materials and adjusting the composition of the final product as desired, which is described in detail in WO 01/32905, which is incorporated herein by reference.

When the biologically active peptides for use in the present invention are formed by fermentation, the starting material may be any product containing the sequences of the desired biologically active peptides as part of its own peptide or protein sequence. The milk protein, especially casein, is preferably used as such or in the form of various preparations. Suitable starting materials also include, for example, various casein-containing dairy products, such as skimmed milk or milk with different fat contents, as such or in the form of milk powder, and sour milk products, such as milk, buttermilk, yoghurt, filet, unripened cheese, etc.

The fermentation can be carried out with any lactic acid bacterium capable of producing the desired peptides from the starting material. Suitable lactic acid-5 bacteria are found, for example, in species belonging to the genera Lactobacillus, Lac-tococcus, Leuconostoc, Streptococcus and Bifidobacterium. The most proteolytic lactic acid bacterium is Lactobacillus helveticus and is therefore particularly suitable for this purpose. A preferred strain of Lactobacillus helveticus is L. helveticus LBK-16H, DSM 13137, which is described in detail in WO 01/32836. Particularly preferred is Lactobacillus helveticus LB 1936, DSM 17754, which is described in detail in patent application FI20065054.

Lactic acid bacteria can be used as pure cultures or mixed cultures, alone or in combination with conventionally used and commercially available acidifying agents. Lactic acid bacteria can also be used in combination with other microorganisms.

The fermentation conditions are selected according to the requirements of the strain used so as to generate a sufficient amount of biologically active peptides to achieve the desired effect. The selection of suitable conditions such as temperature, pH and aeration is within the skill of the art. Conventionally, fermentation is carried out at about 30-45 ° C. The fermentation is allowed to continue until the desired amount of biologically active peptides is formed. Normally this takes about 20-30 hours. During fermentation, a mixture of different peptides is formed. As fermentation proceeds long enough, predominantly relatively small di- and tripeptides such as Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) are obtained. An incubation time of about 22 to 24 hours is preferred.

The resulting cell suspension can be used as such or peptides can be isolated and purified using conventional methods. Concentration, for example by evaporating or drying the cell suspension partially or completely, for example by spreading the suspension on a plate, drying and finally grinding to a well-preserved dry powder, is a preferred treatment.

In addition, treatment of the cell suspension by nanofiltration has proven to be an excellent method that allows the production of active peptides in the same 35 products with the desired mineral composition in endothelial functions such as arterial stiffness. By choosing the type of nanofiltration membrane and the process conditions, it is possible to influence the composition of the product obtained.

Nanofiltration is carried out to a desired range of dry solids content, which may be from about 20 to about 40%, or to an approximate volume / volume ratio of from about 5 to about 20. With nanofiltration, the peptide content of the product is increased. The composition of the final products will, of course, depend on the fermentation conditions used, the optional nanofiltration treatment and any other pre- and post-treatment.

According to the present invention, the tripeptides IPP and VPP and products containing them have surprisingly been shown to reduce arterial stiffness and thus improve endothelial dysfunction. During the 10-week intervention period, the Ambulatory Arterial Stiffness Index (AASI) based on daily measurement of arterial stiffness significantly improved in the test group administered product containing tri-15 peptides compared to IPP and VPP; even in the first non-optimized experiment, the index decreased by about 9 percent compared to the control group. The mean AASI at the end of the intervention period was 0.31 ± 0.15 in the Lactobacillus helveticus group and 0.34 ± 0.17 in the control group.

The products described above can be used as such to achieve the desired effect. The products may also be dried and used in the form of powder or freeze-dried preparation. The products may also be advantageously used in the manufacture of health-promoting foods or other products. Applications as medical or pharmaceutical products are also possible.

In the present specification, the term "foodstuff" has a broad meaning that includes all ingestible products, whether in solid, gelled or liquid form, as well as both finished products and products to which biologically active peptides or a product containing them are added as an additive or as part of the product. Foodstuffs may be, for example, products of the dairy industry or the beverage industry. Typical products include dairy products such as yogurt, butter, quark, milk, sour milk, buttermilk, other sour milk products, unripened cheeses and matured cheeses, snack bar fillings, etc. Another important group includes beverages such as whey drinks, fruit drinks .

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According to the invention, the biologically active peptides or the product containing them are used in an amount sufficient to achieve the desired effect. When using the product obtained by the two-step process described above, the amount used depends mainly on the degree of whey concentration and is, for example, 0.1 to 30%, preferably about 5 to 15%, based on the weight of the final product.

The biologically active peptides or product containing them may be added at the stage of manufacture of the food product or in the finished food product. Thus, the food products in question contain the desired peptides 10 or a product containing them in addition to the other ingredients contained in the corresponding food products, and in terms of taste and behavior, are fully equivalent to these traditional products.

The invention will be explained in detail by the following examples. These examples are intended only to illustrate the invention and should not be construed as limiting the scope in any way. The examples demonstrate the beneficial, beneficial and healing effect of IPP and VPP, alone or in combination, on arterial stiffness by enhancing endothelial function, as well as inexpensive end products for administration of bioactive peptides.

Example 1.

Effect of bioactive product on arterial stiffness

Arterial stiffness can be measured using an ultrasound device or an applanation tonometer, or using a vascular stiffness index (AASI) based on daily measurement. AASI is determined as 1 minus Dias-25 slope of slit or systolic pressure during 24-hour ambulatory monitoring and is a reliable indicator of arterial stiffness (Li Y., Wang, JG, Dolan, E., Gao, PJ, Guo, HF, Nawrot, T .: Ambulatory arterial stiffness index derived from 24-hour ambulatory blood pressure monitoring (Hypertension 2006; 47 (3): 359-64).

In a randomized, placebo-controlled, parallel-group study, 94 hypertensive patients who did not receive any drug therapy were given either Lactobacillus helveticus LBK-16H-fermented milk prepared according to Example 2 or a reference product for 10 weeks. after. At the beginning of the intervention period and the loss bag, a 24 hour ambulatory blood pressure measurement was performed. Mean 11 baseline values for systolic and diastolic blood pressure were 132.6 ± 9.9 / 83.0 ± 8.0 mmHg in the Lactobacillus helveticus group and 130.3 ± 9.6 / 80.2 ± 7.0 mmHg in the control group.

At the end of the 10-week intervention period, systolic 5 and diastolic blood pressure had a greater reduction in Lactobacillus helveticusryh compared to the control group. The effect of treatment on systolic blood pressure (SBP) was -4.1 (95% Cl: -6.6-1.8, p <0.001). The effect of treatment on diastolic blood pressure (DBP) was -1.8 (95% Cl: -3.7 to -0.0, p = 0.048).

The AASI index was determined using ambulatory blood pressure values 10 and analyzed by the method of Li et al., Ibid. The AASI index increases linearly with age in both men and women. Small values of the AASI index are more favorable than large values, so if the value decreases, the arterial stiffness decreases. Mean baseline AASI values were 0.36 ± 0.15 in the Lactobacillus helveticus group and 0.36 ± 0.17 in the control-15 group. At the end of the treatment period, the mean AASIs were 0.31 ± 0.14 in the Lactobacillus helveticus group and 0.34 ± 0.15 in the control group.

During the 10-week intervention period, the AASI index improved statistically significantly in the experimental group (p = 0.043) but not statistically in the control group (p = 0.47) (Table 1).

20 Table 1. Change in AASI index after 10 week intervention period

Merk. Average (2-tailed) _ero_

Test group Change in AASI-0.043 -0.0427 index

Control-Change group AASI-0.474 -0.0195 _index_ 12

Example 2.

Preparation of products useful in the present invention

Lactobacillus helveticus strain LBK-16H, DSM 13137 was grown in MRS broth at 37 ° C for 24 hours and inoculated from milk powder into milk (10%) to form an inoculum. After two cycles of growth, the inoculum (15%) was inoculated into fermentor medium prepared from 9-10% skimmed milk powder and sterilized at 110 ° C for 10 minutes. The fermentation was carried out at 37 ° C for 22-24 hours with constant vigorous stirring. The product (a) may be used as such, dried and / or in finely divided form, or the desired peptides may be isolated therefrom by methods known per se.

The process was repeated using Lactobacillus helveticus strain LB 1936, DSM 17754 and whole milk or buttermilk, respectively, instead of skimmed milk powder to provide the corresponding products b and c.

15 Example 3.

Preparation of a final product useful in the present invention Peptide concentrate

Sulfur containing peptides active in the repair of endothelial dysfunction was prepared by adding about 1% peptide concentrate to commercially available milk. The composition of the product is shown in Table 2, which also compares the composition of a commercially available sour milk product, AB milk, manufactured by Valio Oy.

For Evolus® peptide concentrate, fermentation was performed as described in Example 2. The resulting cell suspension was separated by centrifugation. The whey so pretreated was nanofiltered through a Nanomax-50 membrane at 40 ° C and 30 bar. The whey was filtered until the volume ratio was 9.

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Table 2. Composition of Evolus product and commercial sour milk product (AB-milk, Valio Oy)

Nutrition- Evolus AB Dairy Data / 100 g (200 g portion) _ Energy 260 kJ / 61 kcal 220 kJ / 53 kcal Protein 3.0 g 3.2 g Carbohydrates 12 g 4.4 g of which lactose less than 1.0 g * dietary fiber 0 g 0 g fat 0.1 g 2.5 g calcium 150 mg ** 120 mg potassium 233 mg 170 mg magnesium 13 mg 11 mg sodium 24 mg 39 mg tripeptides Ile-Pro-Pro 1.1 mg 0 _Val -Pro-Pro_1.3 mg_0_ * Over 80% of lactose is enzymatically digested 5 ** 25% of daily recommended intake

Example 4.

Preparation of a final product useful in the present invention Fermented milk beverage Evolus power drink

Fermentation of the Evolus® fermented milk drink effective daily dose was performed as described in Example 2. In addition, 1% of the Evolus ® peptide concentrate prepared as described in Example 3 was added to the fermented milk. The product containing the daily active ingredient should be used as such. The nutritional information of the product is given in Table 3. The other ingredients in the fermented milk drink are pasteurized skimmed milk, milk protein concentrate, thickeners, calcium product (from seaweed), acidity regulator, acids, aromas, vitamins (folic acid, B6, B12) and food.

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Table 3. Composition of Evolus® Fermented Milk Beverage

Nutrition- Evolus Power Drink Information / 100g of Various Berries Contains (Serving 100ml) -Drinking-Energy-260kJ / 61kcal Protein 3.5g Carbohydrates 11g of which lactose less than 1.0g * dietary fiber 0g fat 0.1 g calcium 200 mg ** potassium 410 mg magnesium 15.5 mg sodium 38 mg folic acid 66 pg *** vitamin B6 0.66 pg *** vitamin B12_0.33 pg *** _ * more than 80% of the lactose is enzymatically digested ** 25% of daily intake recommendation *** 33% of daily intake recommendation 5 Example 5.

Preparation of a final product useful in the present invention Soft cheese

Soft cheeses such as cream cheese, cream cheese spread and cottage cheese were made by traditional manufacturing methods. For example, Evolus®-10 cream cheese spread was made by mixing quarg, cream or butter and other ingredients, heat-treated and packaged. Evolus® peptide concentrate prepared according to Example 3 was added to the fat fat blend. The product containing the daily active ingredient should be used as such.

Claims (13)

Use of Ile-Pro-Pro and / or Val-Pro-Pro in the preparation of a preparation intended for the prevention and / or host of endothelial dysfunction. Use according to claim 1, characterized in that a product having Ile-Pro-Pro and / or Val-Pro-Pro is used. Use according to claim 2, characterized in that a product having a large body of casein-derived, low molecular weight peptides is used and which has been prepared by fermenting a starting material containing casein with a lactic acid bacterium. Use according to claim 3, characterized in that a product having a large body of casein-derived low molecular peptides is used and which has been prepared by fermenting a starting material containing casein with the Lactobacillus helveticus strain LBK. -16H, DSM 13137 or with the Lactobacillus helveticus strain LB 1936, DSM 17754, alternate by removing partially or completely the casein and / or other milk proteins and / or lactose and by nanofiltrating a fermented product containing as-received peptides. Use according to claim 2, characterized in that a product containing an acidic composition containing a fresh casein derived, low molecular weight peptide Ile-Pro-Pro and / or Val-Pro-Pro and a live lactic acid bacterium is used. Use according to any of claims 3-5, characterized in that the casein-derived, low molecular weight peptides exhibit a mixture of short chain peptides. Use according to any of claims 1 - 6 for the manufacture of a medical product for the prevention or hosting of disorders and diseases associated with endothelial dysfunction. Use according to any one of claims 1-7, characterized in that the product increases the elasticity of blood vessels. Use according to any one of claims 1-8, characterized in that the final product is an edible product. Use according to claim 9, characterized in that the final product is a dairy, beverage, ready-to-eat, meat processing, bakery or caramel industrial product. Use according to claim 10, characterized in that the final product is a fermented milk product. Use according to claim 10, characterized in that the final product is a beverage, preferably a whey beverage, a fruit drink or a beer. Use according to claim 9, characterized in that the final product is a pharmaceutical industrial product.