JP2023169632A - Food for preventing heart failure and pharmaceutical composition for preventing heart failure - Google Patents

Abstract

To provide a food for preventing heart failure and a pharmaceutical composition for preventing heart failure, each of which includes a substance to act via a different mechanism from conventional ones.SOLUTION: A food for preventing heart failure or a pharmaceutical composition for preventing heart failure includes β-conglycinin as an active ingredient.SELECTED DRAWING: Figure 3

Description

The disclosure of the present application relates to a food for preventing heart failure and a pharmaceutical composition for preventing heart failure.

The heart functions as a pump that pumps blood throughout the body. Heart failure is a state in which this blood pumping function is impaired. Heart failure causes various symptoms throughout the body due to insufficient blood being pumped out. Specific examples of symptoms include palpitations, shortness of breath, difficulty breathing, and swelling.

If heart failure develops, surgical or drug treatment is performed, but it is also important to prevent its onset. Patent Document 1 describes a method for preventing heart failure in which heart wall thickening that is not inhibited by angiotensin-converting enzyme inhibition is suppressed by administering Val Pro Pro or He Pro Pro as an active ingredient.

Patent No. 5292632

Patent Document 1 is characterized by using a tripeptide having a specific structure. However, in the field of functional foods and pharmaceutical compositions, since there are individual differences in the effects achieved, it is desired to search for substances that act by different mechanisms even for the same purpose (disease).

The disclosure in this application has been made to solve the above problems. The present inventors conducted extensive research and newly discovered that β-conglycinin has the effect of suppressing the progression of heart failure.

That is, an object of the disclosure of the present application is to provide a food for preventing heart failure and a pharmaceutical composition for preventing heart failure, which contain β-conglycinin as an active ingredient.

The disclosure of the present application relates to foods for preventing heart failure and pharmaceutical compositions for preventing heart failure, as shown below.

(1) A food for preventing heart failure containing β-conglycinin as an active ingredient.
(2) A pharmaceutical composition for preventing heart failure containing β-conglycinin as an active ingredient.

By using the food for preventing heart failure and the pharmaceutical composition for preventing heart failure disclosed in this application, it is possible to suppress the progression of heart failure.

FIG. 1 is a diagram schematically showing afferent hypertrophy, which is a compensatory mechanism for heart failure. FIG. 2 is a diagram schematically showing the production of heart failure mice used in Examples. FIG. 3 is a graph showing changes in EF, FS, LV MASS, and LVEDd in Example 1 and Comparative Examples 1 to 3. FIG. 4 is a graph showing HW/TL of Example 1 and Comparative Examples 1 to 3. FIG. 5 is a Masson trichrome staining and fibrosis quantitative graph of Example 1 and Comparative Examples 1 to 3. FIG. 6 is a graph showing changes in EF, FS, LV MASS, and LVEDd in Example 2 and Comparative Examples 4 and 5. FIG. 7 is a graph showing HW/TL of Example 2 and Comparative Examples 4 and 5, and Masson trichrome staining and fibrosis quantitative graph of Example 2 and Comparative Examples 4 and 5.

Below, the food for preventing heart failure and the pharmaceutical composition for preventing heart failure disclosed in this application will be explained in detail.

(Embodiment of food for preventing heart failure)
First, an embodiment of the food for preventing heart failure will be described. The food for preventing heart failure is characterized by containing β-conglycinin as an active ingredient. β-conglycinin is a protein contained in soybeans and is known to have effects such as lowering blood lipids (for example, see JP-A-2010-94035). However, the mechanism of action of β-conglycinin that has been newly discovered by the present inventors is that it has a preventive effect on heart failure.

As mentioned above, a condition in which the heart's ability to pump blood is impaired is called heart failure. By the way, myocardial infarction is known as a disease in which the blood pumping function of the heart is reduced. A myocardial infarction occurs when the coronary arteries that supply blood to the myocardium (the muscles that make up the heart) are blocked, resulting in a lack of oxygen in the myocardium. ) is a disease in which the body becomes immobile. By the way, it is known that when a load is placed on the heart, a compensatory mechanism (a force that causes the heart to change and act protectively in response to stress; hereinafter referred to as "remodeling") is activated. . Remodeling occurs in both heart failure and myocardial infarction, but the details of the remodeling are different. More specifically, in the case of myocardial infarction, the infarcted area becomes immobile, so the compensatory mechanism is to increase the overall volume of the heart for blood pumping (preload, when blood returns to the heart). load). Therefore, centrifugal hypertrophy occurs. On the other hand, in heart failure, it takes a load to pump blood (afterload, a load is applied when trying to pump blood). Therefore, in the case of heart failure, a compensatory mechanism works to thicken the walls of the ventricle, resulting in afferent hypertrophy (see Figure 1). As described in the Examples below, in the present application, the administration of β-conglycinin has the effect of suppressing the occurrence of afferent hypertrophy. In addition, in this specification, "heart failure prevention" means suppressing a decline in cardiac function and cardiac hypertrophy. Therefore, "heart failure prevention" involves not only reducing the risk of patients who have not yet developed heart failure developing heart failure in the future, but also preventing patients who have already developed mild heart failure from becoming more serious. (in other words, the treatment of heart failure).

As long as the food for preventing heart failure contains β-conglycinin as an active ingredient, there are no particular restrictions on other ingredients. As β-conglycinin, a commercially available product may be used, or one produced by the method described in JP-A No. 2010-94035 and the like may be used. Foods for preventing heart failure can be provided as functional foods such as foods for specified health uses that have efficacy in preventing heart failure. Considering that foods, such as functional foods, are ingested daily, continuously or intermittently over a long period of time, the amount of intake required to obtain such efficacy is not limited in the case of humans; It is preferable that the amount of β-conglycinin, which is an active ingredient, is contained in food so that it can be ingested in an amount of about 1 to 20 g per day. Although there is no particular restriction on the period of ingestion of foods for preventing heart failure, from the viewpoint of prevention, it is preferable to ingest them for a long period of time. Examples include, but are not limited to, one week or more, two weeks or more, three weeks or more, one month or more, three months or more, six months or more, one year or more.

Foods for preventing heart failure can be in the form of solids, gels, or liquids. Examples include fermented dairy products such as lactic acid bacteria drinks, various processed foods and drinks, dry powders, tablets, capsules, granules, etc., as well as various beverages, yogurt, liquid foods, jellies, candies, retort foods, tablet confections, It can be cookies, castella, bread, biscuits, chocolate, etc. In addition, foods for preventing heart failure contain additives such as sugars, proteins, lipids, vitamins, minerals, flavors, carbohydrates, sweeteners, fragrances, pigments, texture improvers, etc., or mixtures thereof, to improve nutritional balance and flavor. etc. may be improved.

(Embodiment of pharmaceutical composition for preventing heart failure)
Next, embodiments of a pharmaceutical composition for preventing heart failure (hereinafter sometimes simply referred to as a "pharmaceutical composition") will be described. The pharmaceutical composition is characterized by containing β-conglycinin as an active ingredient. The mechanism of action of β-conglycinin is the same as that of foods for preventing heart failure.

Pharmaceutical compositions can be administered locally or systemically. The form of administration is not particularly limited, and either oral administration or parenteral administration may be used. In addition to β-conglycinin, which is an active ingredient, the pharmaceutical composition can also contain a pharmacologically acceptable carrier depending on the dosage form. Examples of carriers include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or dissolution aids, isotonic agents, and pH regulators. , stabilizers, propellants, adhesives, and the like.

The dosage of the pharmaceutical composition varies depending on the patient's weight, age, etc., and is not particularly limited. The dosage may be appropriately determined by a doctor.

The embodiments disclosed in the present application will be specifically described below with reference to examples, but these examples are merely for explaining the embodiments. It is not intended to limit or limit the scope of the invention disclosed in this application.

[Creation of heart failure mice]
Heart failure mice were produced by transverse-aortic constriction (TAC). This will be explained in more detail with reference to FIG. 2. A 9-week-old male wild-type mouse (C57BL/6NCrSlc, purchased from Japan SLC Co., Ltd.) was anesthetized with isoflurane and intubated when breathing became shallow. In addition to abdominal breathing, whether or not intubation was successful was confirmed by observing the movement of the thorax in accordance with the movement of the anesthesia machine. After checking, both arms and legs of the mouse were fixed using masking tape or the like to prevent it from moving, and the skin on the chest was peeled off, followed by the subcutaneous tissue. The surrounding muscles were cut a little, and the cut was made from the upper side of the second rib to the lower side of the third intercostal space just above the sternum. From there, use tweezers to spread the tissue so that the inside of the chest can be seen. When you spread the right and left lobes of the thymus gland, you can see the aortic arch underneath. At this point, the adipose tissue and thymus gland were carefully removed. Once the aortic arch was visible, curved forceps were placed behind the aortic arch. While the aortic arch was still in forceps, the thread from another forceps threaded with 7-0 suture was grabbed with a bent forceps and threaded through the aortic arch. A 27G needle was set perpendicularly to the mouse so that it was above the transverse aorta, tied twice (as indicated by the arrow in Figure 2), and after cutting off the excess thread, the chest was closed. The muscle was sutured with 6-0 sutures and then the skin was sutured with 6-0 sutures as well. They then removed the intubation and checked to see if the mouse's breathing returned.

In the mouse model created by TAC, the blood flow to the whole body is suppressed by ligating the transverse aorta, but because the blood flow is not completely stopped, necrosis and infarcted areas of the myocardium do not occur, but afferent hypertrophy occurs. It can faithfully reproduce the symptoms of heart failure. Therefore, β-conglycinin administered orally or parenterally can reach the heart beyond the transverse aorta via blood, so its effect on heart failure (suppression of cardiac function decline and cardiac hypertrophy) can be accurately confirmed. Histologically, this is accompanied by marked hypertrophy of myocardial cells and fibrosis of the cardiac interstitium. For details of TAC, please refer to “Koitabashi N et al: Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustain. ed pressure overload. J Clin Invest. 2011 Jun; 121 (6): 2301-12. doi: 10 .1172/JCI44824. (hereinafter sometimes referred to as Non-Patent Document 1). The content described in Non-Patent Document 1 is included herein by reference.

[Feed and administration method]
(1) β-conglycinin-containing bait A solid bait containing approximately 20% by mass of β-conglycinin based on the total mass of the bait was prepared.
(2) Control Bait A solid bait containing about 20% by mass of lactic acid bacteria-free Mineral Acid Casein based on the total mass of the bait was prepared.
The baits described in (1) and (2) above were manufactured by Research Diet Co., Ltd. and obtained by requesting that they contain β-conglycinin and casein in the above-mentioned proportions.
The mice were kept in cages, and each mouse was fed about 4 g per day, allowing them to eat freely.

[Peritoneal administration reagent and administration method]
β-conglycinin (obtained from Fuji Protein Research Foundation) was dissolved in physiological saline and administered intraperitoneally every day at a rate of 100 mg/kg/day.

[Mouse echocardiography]
Echocardiography was performed to measure cardiac function over time. The procedure was performed without anesthesia because the anesthetic suppressed cardiac function.
When the mice were fed, echocardiograms were measured before the start of feeding, and at 1 week and 2 weeks after the start of feeding, and TAC surgery was performed at the 2nd week. The degree of cardiac hypertrophy, myocardial weight, and cardiac function were evaluated by measuring echocardiography at 1, 2, and 3 weeks after the operation.
When β-conglycinin was intraperitoneally administered to mice, administration was started 3 days after TAC surgery. In the TAC only group, physiological saline was administered as a control. The degree of cardiac hypertrophy, myocardial weight, and cardiac function were evaluated by measuring echocardiography before TAC surgery and 1 week and 2 weeks after surgery.

The measurement items are as follows. All items are known indicators for evaluating cardiac hypertrophy and cardiac function.
・Left ventricular ejection fraction (EF),
・Left ventricular diameter shortening (FS),
・Left ventricular myocardial mass (LV MASS),
・Measure the left ventricular end diastolic diameter (LVEDd) using M-mode,
- Heart weight measurement (HW/TL): Mice were sacrificed 3 weeks after TAC surgery, heart weight was measured, and the degree of cardiac hypertrophy was evaluated by correcting for tibia length. Note that correction based on body weight would increase the variation, so correction was performed based on tibia length.

[Fibrosis quantification by Masson trichrome staining]
According to the procedure described in "Tissue histology" in the left column of page 2311 of Non-Patent Document 1, paraffin sections of the myocardial tissue of killed mice were stained with Masson trichrome and fibrosis quantification was performed.

<Example 1 and Comparative Examples 1 to 3>
・The group in which TAC surgery was performed using β-conglycinin-containing feed was Example 1 (TAC + β-conglycinin),
・Comparative example 1 (TAC + casein), a group in which TAC surgery was performed using control food;
・Comparative example 2 (Control + β-conglycinin), a group in which β-conglycinin-containing feed was used and no TAC surgery
・Comparative example 3 (Control + casein), a group that used control food and did not undergo TAC surgery
As such, we conducted an experiment.

FIG. 3 is a graph showing changes in EF, FS, LV MASS, and LVEDd in Example 1 and Comparative Examples 1 to 3. FIG. 4 is a graph showing HW/TL of Example 1 and Comparative Examples 1 to 3. FIG. 5 is a Masson trichrome staining and fibrosis quantitative graph of Example 1 and Comparative Examples 1 to 3.

As is clear from FIGS. 3 and 4, feeding the feed containing β-conglycinin as an active ingredient tended to suppress the decline in cardiac function caused by heart failure surgery. Furthermore, as is clear from FIG. 5, feeding the feed containing β-conglycinin as an active ingredient tended to suppress fibrosis.

<Example 2 and Comparative Examples 4-5>
・Example 2 (TAC + β-conglycinin), a group in which β-conglycinin was administered intraperitoneally and TAC surgery was performed;
・Comparative example 4 (TAC), a group in which TAC surgery was performed without intraperitoneal administration of β-conglycinin;
・Comparative Example 5 (Control), a group in which β-conglycinin was not administered intraperitoneally and TAC surgery was not performed.
As such, we conducted an experiment.

FIG. 6 is a graph showing changes in EF, FS, LV MASS, and LVEDd in Example 2 and Comparative Examples 4 and 5. FIG. 7 is a graph showing HW/TL of Example 2 and Comparative Examples 4 and 5, and Masson trichrome staining and fibrosis quantitative graph of Example 2 and Comparative Examples 4 and 5.

As is clear from FIG. 6, intraperitoneal administration of β-conglycinin tended to suppress the decline and deterioration of cardiac function caused by heart failure surgery. Furthermore, as is clear from FIG. 7, intraperitoneal administration of β-conglycinin tended to suppress cardiac hypertrophy and fibrosis caused by heart failure.

From the above results, it was confirmed that oral or parenteral administration of β-conglycinin can suppress the decline in cardiac function and cardiac hypertrophy.

The food and pharmaceutical compositions disclosed in this application can prevent heart failure. Therefore, it is useful in the pharmaceutical industry, food industry, etc.

Claims (2)

A food for preventing heart failure that contains β-conglycinin as an active ingredient. A pharmaceutical composition for preventing heart failure, containing β-conglycinin as an active ingredient.