JP2013133322A - Oxidized ldl binding inhibitor composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cardiovascular disease prophylactic or therapeutic agent.SOLUTION: This oxidized LDL binding inhibitor consists of a compound represented by formula (2), for example. When using the oxidized LDL binding inhibitor composition, binding of oxidized LDL to LOX-1 is inhibited, and uptake of the oxidized LDL via the LOX-1 to the inside of cells such as a vascular endothelial cell, a macrophage, and a smooth muscle cell can be inhibited.

Description

  The present invention relates to a pharmaceutical composition that inhibits the binding of oxidized LDL to LOX-1, which is a lectin-like oxidized low-density lipoprotein receptor, a food composition containing the oxidized LDL binding inhibitor composition, and cardiovascular The present invention relates to a preventive or therapeutic agent for diseases or cancer.

  In recent years, the aging of society has been rapidly progressing in East Asia including Japan. Furthermore, with the improvement of medical technology and the longevity of the people, the center of medical expenses is shifting to the treatment of chronic diseases rather than the conventional acute diseases.

  According to the recent demographic statistics of the Ministry of Health, Labor and Welfare of Japan, the number one death in Japan by disease is malignant neoplasm (tumor and cancer), second is heart disease, and third is cerebrovascular disease. The total number of deaths due to heart disease and cerebrovascular disease is about 27% of the total, which is roughly equivalent to the death rate of malignant neoplasms, about 30% (2008). As for coping with malignant neoplasm, early detection / early treatment is important considering the onset process, and clinical approach is desirable. On the other hand, heart diseases and cerebrovascular diseases are diseases that are located downstream of obesity and arteriosclerosis, which are chronic diseases caused by lifestyle-related diseases, and their treatment also lasts for a long time. In other words, as mentioned above, it is statistically shown that the center of medical expenses has shifted to the treatment of chronic diseases.

  For chronic illnesses, treatment in the form of treatment with long-term medication and guidance on daily living habits is common, but due to the nature of the disease, use a form that can be taken on a daily basis It is a process that allows for a preventive approach from food, but rather how to deal with such a process is desirable.

  Low density lipoprotein (LDL) is known as a risk factor for ischemic heart diseases including myocardial infarction. LDL is originally a lipid protein complex necessary for the transport of plasma lipids, but it contains a lot of unsaturated fatty acids that are susceptible to oxidation and is easily oxidatively modified. In recent years, it has been found that this oxidized LDL (oxidized LDL) causes a change in the function of vascular endothelial cells and is an important factor responsible for pathophysiological activity.

A lectin-like oxidized low-density lipoprotein receptor (LOX-1) was first isolated and identified from vascular endothelial cells by one of the inventors as a receptor that mediates the action of oxidized LDL on vascular endothelial cells. (Non-Patent Document 1). Subsequent studies have confirmed that LOX-1 is expressed not only in endothelial cells but also in macrophages, platelets, vascular smooth muscle cells, and the like (Non-Patent Documents 2 to 4).
The expression of LOX-1 is increased due to diabetes, hypertension, hyperlipidemia and the like, and anti-LOX-1 antibody (anti-human LOX-1 mouse monoclonal antibody TS92) prepared by Tatsuya Sawamura is oxidized LDL. Inhibition of the binding between LOX-1 and LOX-1 restores the decrease in endothelium-dependent relaxation by oxidized LDL, and further suppresses infarct formation after myocardial infarction and intimal thickening after balloon injury. The involvement of LOX-1 has also been suggested in the formation of blood clots, endotoxin-induced inflammatory effects, and the development of stroke, and it is assumed that LOX-1 is involved at various levels in the development of cardiovascular disease (Non-Patent Documents 2, 5 to 10).

  For example, an invention aimed at inhibiting the binding of a ligand to LOX-1 has been reported by Tatsuya Sawamura, one of the inventors of the present invention, as a pharmaceutical composition using an antibody against an oxidized LDL receptor (patent) Reference 1).

  On the other hand, there have been reports so far on compounds that claim efficacy against arteriosclerosis, which is one of chronic diseases. For example, Patent Document 2 reports a thrombus formation inhibitor or platelet aggregation inhibitor containing proanthocyanidins, and Tatsuya Sawamura, one of the present inventors, also used proanthocyanidins as polyphenols having LOX-1 antagonist activity. As reported (Patent Document 3), proanthocyanidins are condensed tannins in which a plurality of flavonoid units are polymerized, and have a relatively large molecular weight. Even if these macromolecular compounds are effective, they are very inefficient in terms of absorption of active ingredients, especially when taken orally. Thus, it is necessary to continuously take a thrombus formation inhibitor or a platelet aggregation inhibitor containing 24 g of an active ingredient per day for 60 kg of an adult male. In addition, with regard to proanthocyanidins, reports have been made of an effect of suppressing an increase in blood sugar or blood pressure, an effect of increasing blood adiponectin concentration, etc. (Patent Documents 4 and 5). There is also a report of a fibrosis inhibitor containing an effective amount of a gallate ester for the purpose of preventing fibrotic thickening that occurs in arteriosclerosis (Patent Document 6). However, although Patent Document 6 describes an ester of gallic acid and a flavonoid, there is no description about the relationship between this compound and LOX-1, and it is unclear.

  Moreover, although vascular system function improvement by catechin and epicatechin which are 1 type of flavonoids is also reported (patent document 7), about the gallate ester compound of catechin and epicatechin mentioned in patent document 7, it is LOX-1. A detailed study has not been conducted on the relationship between In addition, flavonoids are known to suppress the formation and propagation of radicals by forming chelates with metal ions such as iron ions and copper ions (Non-Patent Documents 11 and 12). There are no reports of flavonoids acting on the receptors.

  In addition, although some reports have been made on the extract of green tea as a substance containing gallic acid ester and arteriosclerosis, no investigation has been made on the relationship with LOX-1. For example, Patent Documents 8 to 11 and the like have reported the effect of lowering serum cholesterol levels, and all of them are intended to inhibit the absorption of cholesterol in the intestinal tract. While having a cholesterol synthesis pathway, the arteriosclerotic effect by inhibiting the absorption of cholesterol in the intestine is presumed to be very limited.

  In addition, in recent years, regarding the causal relationship between blood cholesterol level and arteriosclerosis, the Japan Society for Lipid Nutrition has published a new guideline that is different from the conventional view (Non-patent Document 13). At present, it cannot be said that there is an effect of preventing arteriosclerosis and further fundamentally preventing cardiovascular disease.

JP 2010-180212 A JP 2004-238289 A JP 2011-006326 A JP 2003-212783 A JP 2006-182706 A Japanese Patent Laid-Open No. 5-271667 JP-T 2009-501161 JP-A-60-156614 JP-A-62-30711 Japanese Patent No. 2812682 JP 2004-262927 A

Sawamura T, et al. , Nature, 386: 73-77, (1997). Chen M, et al. , Biochem Biophys Res Commun, 282: 153-158 (2001). Kataoka H, et al. , Arterioscler Throm Vasc Biol, 21: 955-960 (2001). Yoshida H, et al. , Biochem J, 334: 9-13 (1998). Mehta JL, et al. , Cir Res 100 (11) 1 634-1642 (2007) Li et al. , J. et al. Pharmacol. Exp. Ther. , 302: 601-605 (2002) Hinagata et al. , Cardiovasc Res, 6 9: 263-271 (2006). Kakutani M. et al. , Et al. Proc Natl Aca d Sci USA. 97: 360-364 (2000) Honjo M. , Et al. Proc Natl Acad S ci USA. 100: 1274-1279 (2003) Inoue N. , Et al. , Clin Chem. 2010 Apr; 56 (4): 550-558. Pietta PG, J Nat Prod. 2000, 63, 1 035-1042 Heater A. Hirsch, et al. , Cancer Cell, 17, 348-361 (2010) Cholesterol Guidelines for Longevity 2010 Edition Chunichi Publisher

  The present invention has been made in view of the above-mentioned background art, and aims at the fundamental prevention and treatment of cardiovascular disease, and is an oxidized LDL receptor expressed by vascular endothelial cells, macrophages and the like. PROBLEM TO BE SOLVED: To provide a highly safe pharmaceutical composition that inhibits binding of 1 to oxidized LDL and other LOX-1 and a ligand, a cardiovascular disease preventive or therapeutic agent containing the composition, and a food composition And

  In order to solve the above-mentioned problems, the present inventors diligently searched for components that inhibit the ability of LOX-1 to bind to oxidized LDL from various natural products. As a result, among the flavonoid gallate esters, a compound with a strong action of this purpose was discovered, and further, a divalent transition metal ion compound was found to be essential for enhancing the binding inhibitory activity of flavonoid gallate esters, The present invention has been completed.

That is, the gist of the present invention is as follows.
[1] The following formula (1):

(In the formula, R _{1 to} R ₄ are H or —CH ₃ , R _{5 to} R ₈ are H, —OH or —OCH ₃ , and R _{1 to} R ₄ may be the same group or different. And R _{5 to} R ₈ may be the same group or different groups.)
An oxidized LDL binding inhibitor composition comprising a flavonoid gallate ester represented by formula (II) and a divalent transition metal ion compound,
[2] The oxidized LDL binding inhibitor composition according to [1], wherein R ₁ and R ₄ are H in the formula (1),
[3] The flavonoid gallate is represented by the following formula (2):

Epicatechin gallate (ECg) and / or the following formula (3):

The oxidized LDL binding inhibitor composition according to the above [1] or [2], which is a catechin gallate (Cg) represented by:

[4] The oxidized LDL binding inhibitor composition according to any one of [1] to [3], wherein the divalent transition metal ion is an iron ion or a copper ion,
[5] A preventive or therapeutic agent for cardiovascular disease comprising the oxidized LDL binding inhibitor composition according to any one of [1] to [4],
[6] A food composition containing the oxidized LDL binding inhibitor composition according to any one of [1] to [4],
About.

  In the present invention, the oxidized LDL binding inhibitory action means the action of inhibiting the binding of oxidized LDL to LOX-1 which is a lectin-like oxidized low density lipoprotein receptor, and specifically, Examples described later The method for inhibiting oxidized LDL binding is evaluated by the method as described in 1).

  In the present invention, the cardiovascular disease means a disease in the heart and blood vessels, and examples thereof include stroke, myocardial infarction, thrombotic disease, inflammatory disease and the like.

  By using the oxidized LDL binding inhibitor composition of the present invention, binding of oxidized LDL to LOX-1 is inhibited, and cells such as vascular endothelial cells, macrophages, smooth muscle cells of oxidized LDL via LOX-1 Uptake into the body can be inhibited. In addition, the excellent processability of the flavonoid gallate ester represented by the formula (1), which is an active ingredient of an oxidized LDL binding inhibitor composition, is easy to apply to food compositions and pharmaceuticals, and is inexpensive and safe. The effect of treating or preventing cardiovascular disease via 1 is exhibited.

FIG. 1 is a graph showing the results of the ability to inhibit oxidized LDL binding to hLOX-1 protein (human-derived recombinant LOX-1 protein) in the presence of ECg and each metal ion in Example 1. The vertical axis shows the relative value of the oxidized LDL binding inhibitory ability of each compound when the oxidized LDL binding ability when no compound is added is 100. A lower relative value indicates a higher ability to inhibit oxidized LDL binding. FIG. 2 is a graph showing the results of the ability to inhibit oxidized LDL binding to hLOX-1 in the presence of ECg and divalent transition metal ions in Example 2. FIG. 3 is a graph showing the results of the ability of ECg or Cg to inhibit oxidized LDL binding to hLOX-1 in the presence of a divalent transition metal ion in Example 3. 4 is a graph showing the results of the ability to inhibit oxidized LDL binding to hLOX-1 in the presence of each flavonoid gallate ester and divalent transition metal ion in Example 4. FIG.

  The oxidized LDL binding inhibitor composition of the present invention has the formula (1) as an active ingredient:

(In the formula, R _{1 to} R ₄ are H or —CH ₃ , R _{5 to} R ₈ are H, —OH or —OCH ₃ , and R _{1 to} R ₄ may be the same group or different. And R _{5 to} R ₈ may be the same group or different groups.)
It is a composition containing the flavonoid gallic acid ester shown by and a bivalent transition metal ion compound.

  The flavonoid gallic acid ester is an ester compound of flavonoid and gallic acid.

  In the present invention, the flavonoid gallic acid ester represented by the above formula (1) is used as an active ingredient, so that it is a monomer as compared with a polymer such as proanthocyanin. There is an advantage that it is easily absorbed into the human animal body.

In the above formula, R _{1 to} R ₄ are H or —CH ₃ , and R _{1 to} R ₄ may be the same group or different groups. R _{5 to} R ₈ may be H, —OH or —OCH ₃ , and R _{5 to} R ₈ may be the same group or different groups.

Among these, as the flavonoid gallate ester represented by the above formula (1), R ₁ and R ₄ are preferably H, and R _{1 to} R ₄ are H, from the viewpoint of expressing a strong oxidized LDL binding inhibitory action. R _{5 to} R ₈ are more preferably H or —OH. Among these, from the viewpoint of having an inhibitory action on oxidized LDL binding, the following formula (2):

And / or the following formula (3):

It is preferable that it is Cg shown by these.

  Many of the flavonoid gallate esters represented by the formula (1) are found in a wide variety of plants including Camellia sinensis (tea). Camellia sinensis has long been eaten in various forms throughout the world, including Japan, as a raw material for beverages and foods. Therefore, the flavonoid gallate ester represented by the above formula (1) is problematic in terms of safety. There is no.

  However, the flavonoid gallate ester represented by the formula (1) has a low content in the camelia sinensis. For example, even ECg, which is considered to be relatively abundant in nature, is only about 10% of all major flavonoids contained in Camellia sinensis (for example, Keiichiro Muramatsu, Tea Science, Asakura Shoten) , P88). Therefore, all of the flavonoid gallate esters represented by the formula (1) are a group of compounds that have so far been neglected for their effects compared to other flavonoids such as catechins.

  The flavonoid gallate ester represented by the formula (1) is preferably used as an active ingredient of the oxidized LDL binding inhibitor composition as it is, but in the oxidized LDL binding inhibitor composition of the present invention, the formula (1) In addition to the indicated flavonoid gallate ester, a divalent transition metal ion compound is mixed.

The divalent transition metal ion compound is a compound capable of releasing metal ions in an aqueous solution. Examples of the metal ions constituting the divalent transition metal ion compound include iron ions, copper ions, nickel ions, zinc ions, cobalt ions, manganese ions, and silver ions. Therefore, iron ions and copper ions are preferable.
Specific examples of the ionic compound include sulfates, nitrates, chlorides, sulfides and hydroxides of the divalent transition metal, but there is no particular limitation.
In the present invention, the divalent transition metal ion compound may be prepared by mixing an ionic compound with the flavonoid gallate.

  The amount of the flavonoid gallate ester represented by the formula (1) and the divalent transition metal ion compound in the oxidized LDL binding inhibitor composition may be any amount that exhibits an effect as an active ingredient. It may be prepared only with components, and may contain other components, and is not particularly limited.

In addition, the molar ratio of the flavonoid gallate ester represented by the above formula (1) and the divalent transition metal ion in the oxidized LDL binding inhibitor composition is from the viewpoint of inhibiting the oxidized LDL binding to LOX-1. 100: 1 to 1:10.
The molar ratio of the divalent transition metal ion compound may be calculated by converting the amount of transition metal in the ionic compound to be used.

The oxidized LDL binding inhibitor composition of the present invention may contain other components as needed in addition to the flavonoid gallate ester and divalent transition metal ion compound represented by the formula (1).
Examples of the component include sugar coating such as sugars such as sucrose, sugar alcohol such as maltitol, coating with gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like. It may be covered with a film of material. In the case of foods, water, alcohol, starch, protein, fiber, sugar, lipid, vitamin, mineral, flavoring, coloring, sweetener, seasoning, stabilizer, preservative, emulsifier, etc. For example, it may be combined with a raw material or a material that is usually blended in a simple food.

  In addition, the oxidized LDL binding inhibitor composition of the present invention can be blended into compositions such as foods and pharmaceuticals using known techniques. In this case, the oxidized LDL binding inhibitor composition of the present invention may be used as it is, but may be blended in various base materials. The type of the substrate is not particularly limited and may be set as appropriate. For example, an oral administration substrate such as a tablet, capsule, candy, gummi, or drink is preferable from the viewpoint that it can be easily blended into foods.

  As a food composition, as a general food, a desired amount of the oxidized LDL binding inhibitor composition is added to various food ingredients and processed by a normal production method, or as a health food or functional food. It can be used in an easy state.

  Examples of the pharmaceutical composition include tablets, powders, granules, capsules, suppositories, injections, liquids, and the like. These include bulking agents, excipients, lubricants, disintegrants, binders, flavoring agents, and the like. At the same time, it may be formulated according to a usual method. These pharmaceutical compositions are used as preventive or therapeutic agents for cardiovascular diseases.

  The daily dose of the oxidized LDL binding inhibitor composition of the present invention varies depending on symptoms, height, weight, age, etc., but the intake amount per adult is 1 to 2000 mg / kg · day, preferably It is preferable to administer to a subject such as a human or non-human animal in 1 to several times so that the dose is 1 to 100 mg / kg · day.

  The oxidized LDL binding inhibitor composition of the present invention is used in humans and non-human animals (eg, monkeys, cows, pigs, horses, sheep, goats, donkeys, camels, rabbits, dogs, cats, mice, mice, guinea pigs, etc.). It can be expected to prevent / treat cardiovascular disease by administration to animals, birds such as chickens, ducks and geese.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the gist of the present invention is not limited thereto.

Example 1
The inhibitory effect of ECg on oxidized LDL binding in the presence of various divalent transition metal ions was evaluated using recombinant hLOX-1 protein.

As the divalent transition metal ion compound, FeSO ₄ , CuSO ₄ , NiSO ₄ , ZnSO ₄ , CoCl ₂ and MnSO ₄ were used.

  Recombinant hLOX-1 protein is the extracellular domain of human-derived LOX-1. Among human LOX-1 cDNA (Genbank: NM002543), a region encoding the extracellular domain (ex-hLOX-1) (61st to 273rd nucleotide sequence) expressed and purified according to a conventional method is used. did. It was confirmed that the recombinant hLOX-1 protein has a binding ability to oxidized LDL, and it was decided to use it as a test LOX-1 preparation by the following ELISA.

ELISA (Enzyme Linked Immunosorbent Assay) was performed using a maxisorp immunoplate (96 well type, manufactured by NUNC). The recombinant hLOX-1 protein purified as described above was adjusted with PBS (−) buffer to 5 μg / mL, and 50 μL was applied to each well. After allowing to stand overnight at 4 ° C., each well was washed twice with PBS (−) buffer at 400 μL × 2 times, and 300 μL of PBS (−) buffer containing 20% immunoblock was applied to each well. After allowing to stand at 25 ° C. for 2 hours, each well was washed twice with PBS (−) buffer in 400 μL × 2, and each transition metal ion concentration was adjusted to 3 μM with 2 μM ECg / 10 mM HEPES / 150 mM NaCl buffer. 50 μL of each purified sample was applied to each well. After standing at 4 ° C. for 1 hour, each well was washed with 400 μL × 3 times with PBS (−) buffer, and oxidized with 10 mM HEPES / 150 mM NaCl / 0.1% BSA adjusted to 1 μg / mL. LDL was applied to each well. After allowing to stand at 4 ° C. for 1 hour, each well was washed with PBS (−) buffer at 400 μL × 3 times, and an anti-ApoB HUC20 antibody was diluted with 10 mM HEPES / 150 mM NaCl / 0.1% BSA in an appropriate amount. 50 μL was applied to each well. After standing at room temperature for 1 hour, each well was washed with PBS (−) buffer 400 × L × 3 times, and Donkey anti-chicken IgY antibody was diluted with 10 mM HEPES / 150 mM NaCl / 0.1% BSA in an appropriate amount. 50 μL was applied to each well. After standing at room temperature for 1 hour, each well was washed with 400 μL × 5 times with PBS (−) buffer, and 3,3 ′, 5,5′-tetramethylbenzidine (TMB) peroxidase-enzyme immunoassay ( 50 μL of EIA) -substrate-kit reagent (Bio-rad) was applied to each well. After an appropriate reaction time, 50 μL of 0.5 MH ₂ SO ₄ was applied to each well to stop the reaction. Finally, detection was performed at 450 nm, and the oxidized LDL binding inhibitory activity (oxidized LDL binding inhibition rate against LOX-1) was quantified. The results are shown in FIG.

  As a result, as shown in FIG. 1, LOX is present in the presence of iron ions, copper ions, nickel ions, and zinc ions as compared with the case where the binding rate of oxidized LDL is 100% (“100% binding” in the figure). Inhibition of oxidized LDL binding to -1 was found. Among them, the most excellent oxidized LDL binding inhibitory activity was found in the presence of iron ions. This is an activity superior to that when no metal ion compound is added (“no metal” in the figure). Similarly, excellent oxidized LDL binding inhibitory activity was also found for copper ions. This indicates that the presence of iron ions and copper ions is useful as an oxidized LDL binding inhibitor composition for ECg.

  In addition, even when Cg was used instead of ECg, the action of inhibiting oxidized LDL binding was confirmed in the presence of iron ions and copper ions.

(Example 2)
The ability to inhibit oxidized LDL binding to hLOX-1 in the presence of ECg and divalent transition metal ions was evaluated.

  The evaluation method was performed in the same manner as in Example 1 except that the divalent transition metal ions were adjusted so that 0.1 to 100 μM of divalent iron or copper ions were present. The results are shown in FIG.

From the results of FIG. 2, it was found that when 2 μM ECg was used, the activity of inhibiting oxidized LDL binding to LOX-1 was exhibited in the presence of 0.1 μM to 100 μM of iron ions. It was also found that when 2 μM ECg was used, the activity of inhibiting oxidized LDL binding to LOX-1 was exhibited in the presence of copper ions of 0.1 μM to 100 μM, particularly 1 μM to 10 μM.
It was also found that when 2 μM ECg was used, the activity of inhibiting oxidized LDL binding to LOX-1 was exhibited in the presence of 3 μM to 10 μM copper ions.
Therefore, although there is a slight difference depending on the type of metal ion, the molar ratio of the flavonoid gallate to the divalent metal ion is preferably 20: 3 to 2:10 in the case of iron ions, and is preferably 2: 3 to 3. It turns out that 2:10 is preferable.

(Example 3)
The ability of ECg or Cg to inhibit oxidized LDL binding to hLOX-1 in the presence of a divalent transition metal ion was evaluated.

  The evaluation method was performed in the same manner as in Example 1 except that divalent iron ions were used as divalent transition metal ions and ECg or Cg was used at a concentration of 0.03 μM to 10 μM. The results are shown in FIG.

  From the results of FIG. 3, it was found that ECg and Cg showed excellent inhibitory activity at a concentration of 0.1 μM or more.

Example 4
The inhibitory action of oxidized LDL binding to LOX-1 by the ECg analog was examined as follows.
The following flavan skeleton:

In EC, ECg which is a flavonoid gallate ester having a gallate ester structure on the C ring and four kinds of analogs of ECg (formula:

ECg3′-O-Me, ECg4′-O-Me, ECg3 ″ -O-Me, and ECg4 ″ O-Me) represented by formula (1) were evaluated for the inhibitory effect on oxidized LDL binding to LOX-1.
In addition, in the evaluation method, it carried out according to Example 1 except having used bivalent iron ion as a metal ion. The results are shown in FIG.

  From the results of FIG. 4, ECg3 ″ -O-Me also found an excellent inhibitory effect on oxidized LDL binding in the presence of iron ions. Although the inhibitory action of ECg3 ″ -O-Me on oxidized LDL binding is lower than that of ECg, it is considered to have an inhibitory action on oxidized LDL binding to LOX-1. This indicates that ECg3 ″ -O-Me is useful as an oxidized LDL binding inhibitor.

In addition, since Non-Patent Documents 2 to 10 show that LOX-1 is related to the onset of cardiovascular disease, an oxidized LDL binding inhibitor capable of inhibiting the action of LOX-1 is present in animals. It can be expected to be used as a prophylactic / therapeutic agent for cardiovascular disease.
Therefore, the oxidized LDL binding inhibitor composition of the present invention is also excellent in the action of inhibiting the binding of oxidized LDL to the oxidized LDL receptor LOX-1 as described above, and has high safety. By continuously ingesting the oxidized LDL binding inhibitor composition of the invention to a subject such as a human or non-human mammal, the binding of oxidized LDL to cells associated with cardiovascular disease such as vascular endothelial cells continues. It can be used as a prophylactic agent that is inhibited to prevent the onset of cardiovascular related diseases in humans and non-human animals, or a therapeutic agent that alleviates the symptoms of the disease.

Claims (6)

Following formula (1):

(In the formula, R _{1 to} R ₄ are H or —CH ₃ , R _{5 to} R ₈ are H, —OH or —OCH ₃ , and R _{1 to} R ₄ may be the same group or different. And R _{5 to} R ₈ may be the same group or different groups.)
An oxidized LDL binding inhibitor composition comprising a flavonoid gallate ester represented by formula (II) and a divalent transition metal ion compound. The oxidized LDL binding inhibitor composition according to claim ₁ , wherein R ₁ and R ₄ are H in the formula (1). The flavonoid gallate is represented by the following formula (2):

Epicatechin gallate represented by the following formula (3):

The oxidized LDL binding inhibitor composition according to claim 1, wherein the catechin gallate is represented by the formula:   The oxidized LDL binding inhibitor composition according to any one of claims 1 to 3, wherein the metal ion constituting the divalent transition metal ion compound is an iron ion or a copper ion.   A preventive or therapeutic agent for cardiovascular disease comprising the oxidized LDL binding inhibitor composition according to any one of claims 1 to 4.   A food composition comprising the oxidized LDL binding inhibitor composition according to claim 1.

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