CN114010627A - Novel pharmaceutical use of a specific proresolving mediator - Google Patents

Novel pharmaceutical use of a specific proresolving mediator Download PDF

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CN114010627A
CN114010627A CN202111205180.3A CN202111205180A CN114010627A CN 114010627 A CN114010627 A CN 114010627A CN 202111205180 A CN202111205180 A CN 202111205180A CN 114010627 A CN114010627 A CN 114010627A
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myocardial hypertrophy
resolvin
tac
delaying
group
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万军
王梦龙
张记收
于君平
潘威
徐瑶
赵蒙蒙
刘剑芳
徐姝婉
叶晶
王震
叶迪
冯勇淇
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Wuhan University WHU
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Abstract

The invention discloses a new application of a special regression-promoting medium medicament, and finds that the special regression-promoting medium injected into an abdominal cavity of a mouse can surprisingly improve the phenomena of myocardial hypertrophy, heart failure and the like caused by an aortic arch constriction surgery, so that the special regression-promoting medium is used for preparing a product for delaying the myocardial hypertrophy, the myocardial hypertrophy induced by pressure load can be delayed, and the diseases of the heart failure or the myocardial hypertrophy and the like can be prevented.

Description

Novel pharmaceutical use of a specific proresolving mediator
Technical Field
The invention belongs to the field of chronic cardiovascular diseases, and relates to application of a special regression-promoting medium in preparation of a product for delaying myocardial hypertrophy or heart failure.
Background
Heart failure (hereinafter referred to as heart failure) is a serious fatal disease that is receiving much attention. The heart failure has high incidence rate as the serious and terminal stage of heart diseases such as coronary heart disease, hypertension and the like, and is one of the most important cardiovascular diseases at present. At present, it is clear that the main mechanism of the occurrence and development of heart failure is myocardial remodeling, and the main pathological changes of the myocardial remodeling include the changes of myocardial hypertrophy, myocardial fibrosis, infiltration of inflammatory cells, release of inflammatory factors and the like, so that the factors finally cause abnormal changes of the heart structure and function, the contraction function and the relaxation function of the ventricles are disordered, and a series of clinical syndromes are caused. Therefore, the key point of clinical treatment of heart failure is to deeply explore the molecular mechanism of cardiac remodeling and search for new therapeutic targets and slow down or reverse cardiac remodeling of patients, and the method has important significance for effectively improving the condition of the patients with heart failure.
At present, the drugs widely used clinically for the treatment of heart failure progression are diuretics, β -blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, and the like. The medicines can improve symptoms and delay the progress of the disease to a certain extent, but various side effects including cough, headache, eruption and the like still exist. And since the mechanism of heart failure has not yet been fully elucidated, there is still a need to further search for a targeted and effective drug for the prevention and treatment of stress-load induced heart failure.
Specialized pro-resolution mediators (SPMs, also known as specialized pro-inflammatory resolution mediators) are a large class of cell signaling factors, and preclinical studies in animal models and human tissues have shown that SPMs act to coordinate resolution of inflammation, in other words, SPMs have potent anti-inflammatory activity (i.e., they reduce neutrophil infiltration), are capable of actively stimulating the removal and disappearance of inflammatory exudates, promoting the clearance of infections, and stimulating wound healing. As a member of the SPM family, Resolvin D1(Resolvin D1, hereinafter RvD1) and Resolvin E1(Resolvin E1, hereinafter RvE1) have been studied extensively to prevent and address the diverse pathological inflammatory responses and tissue destruction and pathogenesis resulting from these responses. The E series resolvins are derived from the long chain n-3 fatty acid eicosapentaenoic acid (EPA) and the D series resolvins are derived from the n-3 fatty acid docosahexaenoic acid (DHA). There is increasing evidence that these compounds act to coordinate the resolution of inflammation during the inflammatory process. However, there are no reports of the regressins D1 and E1 on the retardation of myocardial hypertrophy.
Disclosure of Invention
The invention discovers that the regression-promoting lipid mediators RvD1 and RvE1 can slow down the phenomenon of myocardial hypertrophy caused by pressure load induction and play a role in protecting heart remodeling diseases, so that the RvD1 and the RvE1 can be used for preventing diseases related to the myocardial hypertrophy, including the myocardial hypertrophy, heart failure and the like.
The invention provides the following technical scheme:
in a first aspect, the present invention provides the use of a dedicated proresolving medium in the manufacture of a product for delaying myocardial hypertrophy.
On the basis of the above technical scheme, the specific proresolving medium comprises at least one of resolvin D1 and resolvin E1 or a tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof.
On the basis of the technical scheme, the product for delaying myocardial hypertrophy is used for delaying myocardial hypertrophy under the induction of pressure load.
On the basis of the technical scheme, the product for delaying myocardial hypertrophy is used for delaying myocardial hypertrophy induced by hypertension.
On the basis of the technical scheme, the product for delaying myocardial hypertrophy is used for preventing myocardial hypertrophy or heart failure.
On the basis of the technical scheme, the special regression-promoting medium with effective dose is added into the hypertension medicine for delaying the myocardial hypertrophy.
In a second aspect, the present invention provides a medicament for delaying myocardial hypertrophy comprising a specific proresolving mediator as an active ingredient.
On the basis of the above technical scheme, the specific proresolving medium comprises at least one of resolvin D1 and resolvin E1 or a tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof.
In a third aspect, the invention provides a hypertension drug, which is added with an effective amount of a special regression-promoting medium for delaying myocardial hypertrophy.
On the basis of the above technical scheme, the specific proresolving medium comprises at least one of resolvin D1 and resolvin E1 or a tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof.
The invention has the beneficial effects that:
the special regression-promoting medium can effectively reduce the trend of the myocardial wall thickness of the mice under the induction of pressure load, delay the cardiac remodeling process, prevent the myocardial hypertrophy and prevent the myocardial hypertrophy from entering the heart failure stage.
The special regression-promoting medium can be used as a medicine and a health-care product for preventing and treating the pressure load-induced heart failure, has the double effects of reducing cardiac hypertrophy and cardiac fibrosis and improving cardiac function, has small side effect, and can reduce the medication burden of patients.
Drawings
FIG. 1 shows the stress-load induced myocardial fibrosis in mice by the Polymerase Chain Reaction (PCR) and Western Blot (WB) experimental results of each marker and Smad signaling pathway, wherein FIG. 1A shows the PCR results of Col-1 mRNA, FIG. 1B shows the PCR results of Col-3 mRNA, FIG. 1C shows the PCR results of TGF-. beta.mRNA, FIG. 1D shows the PCR results of CTGF mRNA, FIG. 1E shows the WB protein band, and FIG. 1F shows the quantitative results of Smad 2/3.
Detailed Description
The invention discovers that after a model building operation of a mouse model for chronic myocardial remodeling, by injecting RvD1 and RvE1 into the abdominal cavity of the mouse every other day, the cardiac remodeling and the heart failure caused by an aortic arch constriction operation (TAC) can be surprisingly improved. Thus, there is provided the use of a specific proresolving mediator in the manufacture of a product for delaying myocardial hypertrophy, whereby the specific proresolving mediator is used to prevent heart failure or myocardial hypertrophy.
In the technical solution of the present invention, the chemical structure of the specific proresolving medium comprises: resolvin D1(RvD 1): 7S,8R, 17S-trihydroxy-docosac-4Z, 9E,11E,13Z,15E, 19Z-hexaenoic acid, resolvin E1(RvE 1): 5S,12R, 18R-trihydroxy-eicosa-6Z, 8E,10E,14Z, 16E-pentaenoic acid, and analogs containing the above core structures with similar chemical effects.
In practical applications, the specific pro-resolving mediator may be in the form of a tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, provided that the chemical structure of the compound allows for the presence of such forms.
In the present invention, the above-mentioned "pharmaceutically acceptable salts" refer to salts derived from the corresponding compounds suitable for administration to a subject to achieve the treatment described in the present invention without undue adverse side effects, and mainly include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, such as salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
In the present invention, the above-mentioned "pharmaceutically acceptable salts" also include salts of conventional bases such as alkali metal salts (e.g., sodium salts and potassium salts), alkali metal salts (e.g., calcium salts and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms such as ethylamine, diethylamine, triethylamine, ethyldiisomethylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, benzhydrylamine, N-methylmelamine, arginine, lysine, ethylenediamine and N-methylpiperidine.
In the present invention, the specific pro-resolution vehicles and their analogs may act systemically and/or locally, which may be administered in a suitable manner, such as by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, intra-aural, dermal or scalp routes or as implants or stents.
In the present invention, the specific proresolving vehicle may be included in a composition that may be formulated as a cosmetic composition, a pharmaceutical composition, a food formulation, a food ingredient or supplement, a functional food, a nutritional supplement, a nutraceutical composition (nutraceutical composition) or in an extract of a natural product.
In addition, compositions comprising a specific proresolving mediator may also comprise other ingredients. For example, the composition comprising the specialized proresolving medium is mixed, dissolved, emulsified (e.g., in an oil/water, water/oil, or double emulsion), or suspended in a matrix or base. The matrix or base may be, for example, an edible oil, such as an omega-3 PUFA containing oil, an omega-3 PUFA concentrate containing high levels of EPA, or del a, or a mixture of EPA and del a, or another edible oil suitable for consumption or administration. The matrix or binder may also be water or an aqueous buffer. Compositions comprising SPM may also be prepared in liposomes, nanoparticles or microparticles.
Compositions comprising specific proresolving mediators can also be converted into the administration forms described. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifying and dispersing agents or wetting agents (e.g., sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), coloring agents (e.g., inorganic pigments, e.g., iron oxide), and masking flavors and/or odors, and the like.
In the present invention, cardiac hypertrophy is characterized by an increase in size of cardiac myocytes, a broadening of cell diameter, and an increase in length at the cellular level; at the tissue level, this is manifested by an increase in ventricular mass, with the sarcomeric replication arranged in a parallel architecture, with central hypertrophy throughout. (evaluation and comparison of myocardial hypertrophy and heart failure of mice caused by constricting aortic arch to different degrees, Wangyngying, China emergency medical journal, No. 25, No. 8 in 2016, No. 1027, No. 1030, and No. 8 in 2016).
Further, the heart failure or myocardial hypertrophy is pressure load induced heart failure or myocardial hypertrophy.
Further, the heart failure is heart failure induced by hypertension or myocardial hypertrophy.
The hypertension refers to the systolic pressure of the arterial blood in the body is more than or equal to 140 mm Hg, and the diastolic pressure is more than or equal to 90 mm Hg.
Further, the heart failure or cardiac hypertrophy is clinically manifested heart failure or cardiac hypertrophy.
Further, the heart failure or cardiac hypertrophy is subclinical manifestation of heart failure or cardiac hypertrophy.
A. Definition of
In order that the invention may be better understood, certain terms are first defined and certain accepted definitions are provided, as well as other definitions that will be set forth in the detailed description.
As used herein, the use of "a", "an" and "the" includes both the singular and the plural.
As used herein, "analog" refers to any molecule having the basic structural components of the parent compound. Also, the compounds disclosed herein may contain one or more asymmetric centers, i.e., where asymmetric carbon atoms are present, multiple stereoisomers may be present.
As used herein, the term "agent" includes any compound, composition to be tested for efficacy in the methods disclosed herein.
One skilled in the art will be able to readily determine what is a therapeutically effective amount or an effective amount.
As used herein, the term "unsaturated fatty acid" refers to a fatty acid comprising at least one double or triple bond. Such fatty acids use the greek letter to identify the position of the double bond. The "alpha" carbon is the carbon closest to the carboxyl group, while the "omega" carbon is the last carbon in the chain. For example, linoleic acid and gamma-linolenic acid (referred to as LA and GLA, respectively) are omega-6 fatty acids because they have a double bond six carbon atoms away from the omega carbon. Alpha-linolenic acid is an omega-3 fatty acid because it has a double bond three carbon atoms away from the omega carbon.
B. Main body
As used herein, the terms "subject" and "patient" are used interchangeably, and the terms "subject" and "subjects" refer herein to an animal, such as a mammal, including non-primates (e.g., pigs, cows, horses, donkeys, goats, camels, cats, dogs, guinea pigs, rats, mice, sheep) and primates (e.g., monkeys, gorillas, chimpanzees, and humans). In one embodiment, the subject of a chronic cardiovascular disease that is being treated or prevented that would benefit from improved cardiomyocyte hypertrophy, reduced cardiomyocyte fibrosis is a mammal, and preferably a human.
The term "cardiovascular disease that would benefit from improved cardiomyocyte hypertrophy, reduced cardiomyocyte fibrosis" includes a range of chronic cardiovascular diseases due to the progression of the degree of cardiac remodeling, including mainly hypertrophic cardiomyopathy and end-stage heart failure.
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1
1. Experimental animals and breeding:
healthy C57BL/6 mice, male, 6 weeks old, purchased from life river (beijing) laboratory animal science and technology limited, housed in the standardized laboratory animal center (SPF grade) of the people hospital, university of wuhan, under the conditions: the temperature is 22-24 deg.C, the humidity is 40-70%, the illumination time is 12h, and the drinking water can be freely taken.
2. Laboratory instruments and reagents:
17(R) -RvD1, available from Cayman Chemical (Anneaberg, Missippi, USA);
MyLab 30CV ultrasound system (Biosound Esaote, Inc.);
quantitative digital Image analysis system (Image-Pro Plus, version 6.0);
fluorescence imaging system (Olympus Dx51) and corresponding software (DP2-BSW, version 2.2).
3. The animal model building step:
32 male C57BL/6 mice with uniform development and consistent growth performance and weight of about 24-26g are selected and freely fed with food and water. One week after acclimation feeding, randomized into sham (8), TAC + RvD1 (8) and TAC + RvE1 (8). No water is forbidden after 8 hours of fasting before operation. The mice were weighed at the time of surgery, and the aortic arch of the C57BL/6 mice was narrowed by about 0.4 mm in diameter using aortic transection narrowing to establish pressure load-induced myocardial hypertrophy and heart failure model mice.
Heart failure and myocardial hypertrophy models:
(1) intraperitoneal injection is carried out on 3% pentobarbital sodium according to the dose of 90mg/kg to anesthetize a mouse, the chest and the axillary hairs of the mouse are shaved by a mouse shaver (the operation area is fully exposed), the operation area is disinfected by iodine tincture and 75% ethanol, then the mouse is placed on a heating pad of the mouse to maintain the body temperature, and TAC operation can be carried out when no reaction is caused by toe clip detection.
(2) Tracheal intubation: and (3) turning on an external light source and a microscope switch, turning on a breathing machine, setting parameters (the breathing frequency is 110bpm), inserting the tracheal intubation into the trachea of the mouse along the glottis, taking down the mouse and connecting the breathing machine, observing the breathing condition of the mouse, and indicating that the intubation is successful due to the fact that the thoracic contour fluctuation is consistent with the breathing machine frequency, so that the TAC operation can be carried out.
(3) The entire set of surgical instruments should be autoclaved prior to surgery and operated under a clean bench to ensure that a sterile environment is maintained during the surgical procedure. The anterior teeth were hooked with rubber bands to fix the neck, the tongue was gently moved aside with curved forceps, and then tracheal intubation was performed and connected to a ventilator at a cycle rate of 125-. The neck and chest were wiped with a 75% alcohol solution and a 2 cm long incision was made along the midline of the neck with a scalpel. Saline is instilled at the exposed muscle tissue to keep moist, a partial thoracotomy is performed microscopically on the second rib, and the sternum is retracted using a chest retractor. The thymus and adipose tissues were gently separated from the aortic arch with forceps, exposing the aortic arch.
(4) Surgery for narrowing the aortic arch:
TAC group, TAC + RvD1 group, and TAC + RvE1 group: a small section of 6.0 silk suture was placed between the innominate artery and the left carotid artery and two loose knots tied around the aortic arch. The thickness of use is 271/2The blunt needle is placed in parallel on the aortic arch, the two knots are quickly tied and the needle is removed to complete the 0.4 mm contraction;
the sham operation group: the above procedure was performed without using silk threads for constriction.
(5) Closing the chest: after the surgery for narrowing the aortic arch is completed, the thoracic cavity is closed by completely suturing the thoracic cavity opening (ensuring no gap and no dislocation) by using 6.0 absorbable suture and a pure interrupted suture method, and each layer of muscle and skin is sutured layer by layer from inside to outside.
(6) And (3) postoperative management: to prevent postoperative infection, the surgical suture site was wiped with iodine tincture. To prevent post-operative pain, mice were injected intraperitoneally with buprenorphine (0.1 mg/kg body weight); after surgery, the animals were placed on a heating pad, closely focused on various vital signs of the animals until they recovered sufficient consciousness to be able to move freely and feed freely, and placed in a recovery cage.
4. Color ultrasonic Doppler real-time cardiac imaging of small animals
The heart function of the mice was measured in real time using the MyLab 30CV color ultrasound Doppler real-time Effect system of Biosound Esaote corporation to detect the Left ventricular end diastolic diameter (LVIDd, unit mm), the Left ventricular end systolic diameter (LVIDs, unit mm), the diastolic ventricular interval thickness (IVSd, unit mm), the Left ventricular ejection fraction (EF, unit%), the Left ventricular minor axis shortening (FS, unit%). The monitoring time was week 4 after TAC surgery. To investigate the effect of RvD1 and RvE1 on the cardiac contractility and heart rate of rats.
After weighing, mice were anesthetized with pentobarbital. The anesthesia depth is confirmed by testing the tail reflection, and the mouse can keep autonomous and stable breathing after the anesthesia takes effect. Then removing hair of the precordial region of the rat by using an animal hair cutter and a hair removing liquid, enabling the rat to be in a supine position and fixed on a self-contained constant temperature system of an ultrasonic system so as to maintain the body temperature of the animal, and coating a proper amount of ultrasonic coupling agent on the chest examination region to be about 2.5mm in thickness. The probe of the ultrasonic instrument is placed on the long-axis section of the left ventricle beside the sternum of the mouse, and the two-dimensional image of the left ventricle is acquired to obtain the parameters such as the wall thickness, the diameter in the cavity and the like, so that the related parameters of the contraction function are calculated. And then, placing the probe at the apex of the heart to obtain a standard apex four-chamber section, obtaining the spectrum of the forward blood flow of the mitral valve in the optimal diastole, and recording data more than ten cardiac cycles so as to obtain the relevant diastolic parameters. When ultrasonic examination is performed, the movement should be as gentle as possible, so as to avoid heart deformation and bradycardia caused by pressing the thoracic cavity of the rat. For data statistics, the sonographer randomly selected three consecutive cardiac cycles and averaged.
5. Tissue detection
After the ultrasonic index detection is finished, CO is used2Anesthetizing the mice, cutting the chest of the mice, removing the heart, placing in 4 ℃ pre-cooled PBS (phosphate buffer saline) buffer, removing excess blood, and allowingHearts were perfused extensively with pre-cooled PBS buffer (pH 7.4). After rapidly cutting off tissues around the heart, large blood vessels and atria, sucking dry the heart surface perfusion liquid by using filter paper, weighing by using a one-ten-thousandth electronic balance and recording as the weight of the heart; thereafter calculating the whole Heart weight index (HW/rT) ═ Heart weight (g)/right tibia length (cm) (Heart weight/rT); heart Body mass index (HW/BW) ═ Heart weight (g)/mouse weight (g) (Heart weight/Body weight).
6. Screening packets
Grouping: 32 mice were randomly divided into 4 groups: sham (Sham, n ═ 8), TAC (TAC, n ═ 8) and TAC +17(R) -RvD1 (n ═ 8) and TAC + RvE1 (n ═ 8). Aortic transection stenosis (TAC) or sham surgery were performed, respectively. In the TAC +17(R) -RvD1 and RvE1 groups, 17(R) -RvD1 and RvE1 (2. mu.g/kg, i.p.) were injected. The sham operation group and the TAC group were injected once every other day before and after the TAC operation, and the sham operation group and the TAC group were injected with the same volume of physiological saline. TAC post-surgery 4 weeks echocardiography, followed by cervical dislocation to sacrifice mice.
In the experimental process, except for different administration schemes, other management modes of the mice in the above groups are the same.
7. Data statistics
Statistical analysis was performed using GraphPad Prism 8 and data calculated as mean ± standard deviation. The detection results of all the above experiments at each time point were analyzed by one-way ANOVA variance, and P < 0.05 was considered as a significant difference.
The experimental results are as follows:
after 4 weeks after aortic arch constriction, compared with a pseudo-operation group, pathological sections of the TAC group indicate that myocardial cells have obvious hypertrophy, and ultrasonic Doppler indicates that the heart function of the TAC group is obviously reduced. However, after the regressins RvD1 or RvE1 were used, a significant improvement in the cardiac function of the mice was observed.
TABLE 1 mouse 4 week echocardiography test results
Artificial operation group TAC group Group TAC + RvD1 TAC + RvE1 group
IVSd(mm) 0.96±0.11 1.10±0.29 1.04±0.17 1.02±0.11
LVIDd(mm) 3.68±0.40 4.56±0.15* 4.42±0.33# 4.16±0.26#
LVIDs(mm) 2.36±0.29 3.86±0.29* 3.26±0.29# 3.14±0.32#
EF(％) 70.22±5.72 35.23±10.71* 57.44±5.79# 54.76±6.07#
FS(％) 35.80±5.27 14.60±5.33* 26.25±3.17# 24.65±4.09#
Remarking: p < 0.05 in the TAC group compared to the sham group; compared with the TAC group, the TAC + RvD1/RvE1 group has a # P of less than 0.05.
As shown in Table 1, the left ventricular end-diastolic and end-systolic inner diameter thicknesses (LVIDd, LVIDs) of the TAC group mice showed a tendency of hypertrophy (P < 0.05) at week 4 after the operation, compared with the sham operation group. Compared with the TAC group mice, the thickness of the left ventricle inner diameter at the end diastole and the end systole of the administration group mice is obviously reduced (P < 0.05). The left ventricular diastolic ventricular septal thickness (IVSd) of the mice in the TAC group tended to increase, but there was no significant difference (P > 0.05), compared to the sham group. Compared with the TAC group, the IVSd of the mice in the administration group has no significant difference (P is more than 0.05), but has a decreasing trend. By the end of the experiment, no TAC group mice showed obvious left ventricular chamber enlargement. Compared with a sham operation group, parameters such as left ventricular Ejection Fraction (EF) and left ventricular short axis shortening rate (FS) of mice in an operation group show a remarkable reduction trend (P < 0.05) of the systolic and diastolic functions of the mice, so that the mice in a TAC group have reduced systolic and diastolic functions, and compared with the TAC group, the mice in an administration group have obvious improvements in EF and FS, so that the regression of lipid mediators and analogues thereof, particularly RvD1 and RvE1, can increase the systolic function, reduce the trend of the thickness of the wall of a myocardial chamber and prevent a cardiac remodeling process.
TABLE 2 week 4 tissue weight measurement results
Artificial operation group TAC group Group TAC + RvD1 TAC + RvE1 group
HW/BW(mg/g) 4.54±0.19 6.71±0.49* 5.81±0.35# 5.34±0.19#
HW/TL(mg/cm) 6.61±0.26 10.76±0.83* 8.69±0.93# 8.39±0.45#
Remarking: p < 0.05 in the TAC group compared to the sham group; compared with the TAC group, the TAC + RvD1/RvE1 group has a # P of less than 0.05.
As can be seen from Table 2, compared with the sham-operated group, the heart body weight index and the whole heart body weight index of the mice in the TAC group are both significantly improved (P is less than 0.05), which is about 150% of the mice in the sham-operated group; compared with the TAC group, the corresponding indexes of the mice in the administration group are obviously improved, and the significant difference is realized (P is less than 0.05). Thus, it was demonstrated that the regression-promoting lipid mediators and their analogs, especially RvD1 and RvE1, improve pressure load-induced left ventricular hypertrophy and prevent the cardiac remodeling process.
The pressure load induced myocardial fibrosis in mice is shown in figure 1. Compared with a sham operation group, the TAC group mice have obviously increased myocardial fibrosis markers (Col-1, Col-3, TGF-beta and CTGF) at the 4 th week after TAC operation, and myocardial fibrosis related Smad pathways show an increasing trend and have significant difference (P is less than 0.05). Compared with the operation group, after the drug intervention, the myocardial fibrosis markers and related proteins of the mice show obvious improvement, which indicates that the regression-promoting lipid mediators and the analogues thereof, especially RvD1 and RvE1 can obviously improve the myocardial fibrosis induced by the pressure load of the mice and slow down the development of cardiac remodeling.
In conclusion, the regressins RvD1 and RvE1 can be used for preventing and treating myocardial hypertrophy and heart failure diseases induced by pressure load, and particularly can improve the cardiac function, stop the cardiac remodeling process and prevent the cardiac remodeling from entering the heart failure stage of mice induced by hypertension. Resolvins RvD1 and RvE1 can be used as medicines and health-care products for preventing and treating pressure load induced heart failure, have double effects of reducing cardiac remodeling and improving cardiac function, have small possible side effect and can reduce the medication burden of patients.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (10)

1. Use of a dedicated proresolving medium in the manufacture of a product for delaying myocardial hypertrophy.
2. Use according to claim 1, characterized in that: the specialized proresolving mediator includes at least one of resolvin D1, resolvin E1, or a tautomer, solvate, hydrate, pharmaceutically acceptable salt thereof.
3. Use according to claim 1, characterized in that: the product for delaying myocardial hypertrophy is used for delaying myocardial hypertrophy under the induction of pressure load.
4. Use according to claim 1, characterized in that: the product for delaying myocardial hypertrophy is used for delaying myocardial hypertrophy induced by hypertension.
5. Use according to claim 1, characterized in that: the product for delaying myocardial hypertrophy is a medicament for preventing and treating myocardial hypertrophy or heart failure.
6. Use according to claim 1, characterized in that: an effective amount of a specialized regression-promoting vehicle is added to a hypertensive medication for delaying myocardial hypertrophy.
7. The medicine for delaying myocardial hypertrophy is characterized in that: comprising a specific proresolving mediator as an active ingredient.
8. The medicament for delaying myocardial hypertrophy according to claim 7 wherein: the specialized proresolving mediator includes at least one of resolvin D1, resolvin E1, or a tautomer, solvate, hydrate, pharmaceutically acceptable salt thereof.
9. A hypertension drug, which is characterized in that: an effective amount of a specialized regression-promoting mediator is added to delay myocardial hypertrophy.
10. The hypertension drug according to claim 9, wherein: the specialized proresolving mediator includes at least one of resolvin D1, resolvin E1, or a tautomer, solvate, hydrate, pharmaceutically acceptable salt thereof.
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Citations (2)

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US20080280980A1 (en) * 2005-11-18 2008-11-13 Trustees Of Boston Univeristy Treatment and Prevention of Bone Loss Using Resolvins
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WO2020115231A1 (en) * 2018-12-06 2020-06-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and compositions for treating cystic fibrosis airways

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