Application of meroterpenoid I in preparation of anti-heart failure medicine

Abstract

The invention discloses an application of a meroterpenoid compound I in preparation of an anti-heart failure medicine. The meroterpenoid I separated and purified from marine fungi Aspergillus terreus GZU-311 is used for treating a mouse heart failure model induced by adriamycin or coronary artery left anterior descending branch ligation, and it is found that the meroterpenoid I can improve the heart function of a mouse, reduce myocardial cell damage, inhibit myocardial connective tissue thickening and improve myocardial cell arrangement disorder, and the meroterpenoid I can be used for treating the heart failure of the mouse induced by adriamycin or coronary artery left anterior descending branch ligation, so that the meroterpenoid I can be used for treating the heart failure of the mouse induced by adriamycin or coronary artery left anterior descending branch ligation. Inflammatory cell infiltration is reduced, and the effect of resisting heart failure is achieved. Therefore, the invention provides the application of the meroterpenoid I in preparing the heart failure resisting medicine. According to the invention, medicine source molecules for treating heart failure are enriched, and development and clinical treatment of anti-heart-failure medicines are facilitated.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and specifically relates to the application of a heteroterpenoid compound I in the preparation of an anti-heart failure drug. Background Art

[0002] Heart failure, abbreviated as HF, refers to a pathophysiological state and clinical syndrome in which the heart's pumping function is reduced and it cannot adequately discharge the blood returning from the veins to meet the metabolic needs of body tissues. It is characterized by high re-hospitalization rate, high disability rate and high mortality rate.

[0003] At present, the commonly used anti-heart failure drugs in clinical practice mainly include renin-angiotensin system inhibitors, anti-aldosterone drugs, diuretics, beta-receptor blockers and cardiac glycosides. Although the above drugs have certain anti-heart failure effects in clinical practice, long-term use of these drugs will produce drug resistance and a series of side effects and adverse reactions, such as postural hypotension, depression, increased blood lipids, hypoglycemia, peripheral circulatory disorders, fatigue and bronchial spasm, inhibition of myocardial contractility and conduction block. Therefore, it is urgent to find new drug source molecules to replace existing clinical drugs to solve the patient's tolerance to existing anti-heart failure drugs and the adverse reactions caused by existing anti-heart failure drugs.

[0004] The secondary metabolites of marine fungi are an important part of natural products. They are sustainable, environmentally friendly, rich and diverse metabolites, and have few side effects. They are an important source for natural drug screening. At the same time, the secondary metabolites of marine fungi have a wide range of physiological activities, such as antibacterial, anti-tumor, anti-fibrosis, anti-Alzheimer's disease, anti-heart failure, anti-heart failure and enzyme inhibition, which inject new impetus into the innovation of modern drugs and the research and development of innovative drugs. At present, the search for new drug-derived molecules from marine fungi has become a hot topic of international and domestic research.

[0005] Although the development of cardiovascular disease is closely related to inflammation, myocardial cell fibrosis, etc., not all compounds with anti-inflammatory or anti-fibrotic effects can be used to treat heart failure. For example, drugs prepared from thiazolidinediones can inhibit kidney inflammation, inhibit kidney cell fibrosis, and improve kidney microcirculation (DOI: 10.3969 / j.issn.1672-6170.2009.01.044.). However, such drugs may cause water and sodium retention, excessive body fluids, and induce or aggravate heart failure, increasing the risk of death from heart failure or cardiovascular disease. Although marine fungi are rich in secondary metabolites, it is not easy to obtain compounds with anti-heart failure effects from them. Summary of the invention

[0006] In view of the above-mentioned problems in the prior art, the present invention provides a terpenoid compound that can be used to prepare an anti-heart failure drug, namely, the terpenoid compound I of the present invention.

[0007] The first object of the present invention is to provide the use of heteroterpenoid compound I in the preparation of anti-heart failure drugs.

[0008] The second object of the present invention is to provide a drug for treating heart failure.

[0009] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0010] The present invention uses the heteroterpenoid compound I isolated from the fermentation culture of the marine fungus Aspergillus terreus GZU-311 to treat the mouse heart failure model induced by doxorubicin or ligation of the left anterior descending coronary artery, and finds that the heteroterpenoid compound I has an anti-heart failure effect. Therefore, the present invention claims the use of the heteroterpenoid compound I in the preparation of an anti-heart failure drug.

[0011] Specifically, the structural formula of the heteroterpenoid compound I is shown in formula (I):

[0012]

[0013] Specifically, the heteroterpenoid compound I can improve cardiac function.

[0014] Specifically, the improvement of cardiac function means that the terpenoid compound I can improve cardiac ejection fraction and short-axis shortening rate.

[0015] Specifically, the heteroterpenoid compound I can reduce myocardial cell damage.

[0016] Specifically, the heteroterpenoid compound I can inhibit the thickening of myocardial connective tissue.

[0017] Specifically, the heteroterpenoid compound I can improve the disordered arrangement of cardiomyocytes.

[0018] Specifically, the heteroterpenoid compound I can reduce inflammatory cell infiltration.

[0019] Specifically, the heart failure is chronic heart failure or ischemic heart failure.

[0020] Specifically, the heart failure is doxorubicin-induced heart failure.

[0021] Specifically, the heteroterpenoid compound I is separated and purified from the fermentation culture of the marine fungus Aspergillus terreus GZU-311.

[0022] Specifically, the culture medium used for fermentation culture is a solid corn culture medium prepared by mixing corn and seawater.

[0023] Specifically, the preparation method of the heteroterpenoid compound I comprises the following steps:

[0024] S1. Preparing seed solution of marine fungus Aspergillus terreus GZU-311;

[0025] S2. The seed solution prepared in S1 is inoculated into a solid corn culture medium to obtain a fermentation culture;

[0026] S3. The fermentation culture obtained by S2 was extracted with methanol 2 to 5 times, the extract was concentrated, and the concentrated extract was extracted with ethyl acetate to obtain a crude ethyl acetate extract;

[0027] S4. The crude ethyl acetate extract obtained in S3 is separated by normal phase silica gel chromatography, and then gradient eluted with a petroleum ether / ethyl acetate mixed solution with a petroleum ether volume fraction of 10%, 20%, 30%, 40%, 50%, 60% and 70%, respectively, and 40% of the petroleum ether / ethyl acetate eluate is collected and then separated and purified by silica gel, gel and C-18 reverse phase column chromatography separation techniques to obtain the terpene compound I.

[0028] Specifically, the marine fungus Aspergillus terreus GZU-311 strain described in S1 was deposited in Guangdong Provincial Microbiological Culture Collection Center on December 17, 2019, with the deposit number GDMCC No: 60789.

[0029] Specifically, the preparation method of the seed solution in S1 is: inoculate the marine fungus Aspergillus terreusGZU-311 into a slant culture medium for cultivation, and then inoculate into a liquid culture medium for cultivation to obtain a seed solution; the culture temperature is 28°C to 35°C, and the culture time is 4 to 10 days.

[0030] More specifically, the culture temperature was 30°C and the culture time was 6 days.

[0031] Specifically, S2 is to inoculate the seed liquid prepared in S1 into a solid corn culture medium for static culture to obtain a fermentation culture; the culture temperature is 28° C. to 35° C., and the culture time is 30 to 60 days.

[0032] More specifically, the culture temperature was 30°C and the culture time was 60 days.

[0033] Specifically, the formula of the slant culture medium described in S1 is: by mass ratio, 0.3% glucose, 0.1% yeast extract, 0.1% to 0.5% peptone, 1.5% to 2.5% agar, 1.5% to 4% sodium chloride, and water to 100%.

[0034] More specifically, the formula of the slant culture medium in S1 is: by mass ratio, 0.3% glucose, 0.1% yeast extract, 0.5% peptone, 2.5% agar, 3% sodium chloride, and water to 100%.

[0035] Specifically, the formula of the solid corn culture medium described in S2 is: corn: seawater = 1:1-2 in mass ratio.

[0036] More specifically, the formula of the solid corn culture medium described in S2 is: corn: seawater = 1:1 in mass ratio.

[0037] Specifically, the number of methanol extractions in S3 is 3 times.

[0038] The present invention provides a drug for preventing heart failure, which contains the heteroterpenoid compound I of the present invention or a pharmaceutically acceptable salt thereof.

[0039] Specifically, the drug also includes terpenoid compound I or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0040] Specifically, the heteroterpenoid compound I can be administered alone or in the form of a pharmaceutical composition. The pharmaceutical composition can be formulated into various suitable pharmaceutical preparations according to the administration route.

[0041] Optionally, the pharmaceutical preparation is an oral preparation, an injection preparation or an external transdermal preparation.

[0042] Specifically, the oral preparation can be made into any oral acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used in the tablet generally includes lactose and corn starch, and lubricants such as magnesium stearate can also be added. The diluent used in the capsule preparation generally includes lactose and dry corn starch. The aqueous suspension is usually used by mixing the active ingredient with a suitable emulsifier and suspending agent.

[0043] Optionally, some sweeteners, aromatics or coloring agents may be added to the above oral preparations.

[0044] Specifically, the injection preparation includes liquid injection, powder for injection or tablet for injection. The injection preparation can be used in the form of a sterile injection preparation, including sterile injection water or oil suspension or sterile injection solution. As optional carriers and solvents used in the injection preparation, include water, Ringer's solution isotonic sodium chloride solution and sterilized non-volatile oils such as monoglycerides and diglycerides.

[0045] Specifically, the topical transdermal preparation includes spray, gel, emulsion, ointment, lotion, cream or gel patch. Wherein, the carrier of the ointment includes but is not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water. The carrier of the lotion or cream includes but is not limited to: mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0046] Specifically, the pharmaceutically acceptable excipients include one or more of a drug carrier, a surfactant, a buffer substance, a disintegrant, a binder, a filler, a lubricant, an excipient, a solubilizer, a flavoring agent, and a coloring agent.

[0047] Specifically, the pharmaceutical preparation can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, topical and parenteral administration; wherein, parenteral administration includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and / or intracranial injection or infusion, or administration via an explanted reservoir.

[0048] Specifically, the pharmaceutical preparation is preferably administered orally, intraperitoneally or intravenously.

[0049] It should also be pointed out that the dosage and method of use of the terpene compound I described in the present invention depend on many factors, including the patient's age, weight, gender, natural health status, nutritional status, activity strength of the compound, time of administration, metabolic rate, severity of the disease and the subjective judgment of the treating physician.

[0050] The present invention has the following beneficial effects:

[0051] The present invention uses the terpenoid compound I separated and purified from the marine fungus Aspergillus terreus GZU-311 to treat a mouse heart failure model induced by doxorubicin or left anterior descending coronary artery ligation, and finds that the terpenoid compound I can improve the cardiac function of mice, reduce myocardial cell damage, inhibit myocardial connective tissue thickening, improve myocardial cell disorder, and reduce inflammatory cell infiltration. Therefore, the present invention provides the use of the terpenoid compound I in the preparation of an anti-heart failure drug. The present invention enriches the drug source molecules that can be used to treat heart failure, contributes to the development of anti-heart failure drugs and their clinical treatment, and has good clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 These are cardiac ultrasound images of the mouse heart failure model induced by doxorubicin and the mouse heart failure model treated with the terpenoid compound I.

[0053] Figure 2The figures are the cardiac function test results of the mouse heart failure model induced by doxorubicin and the mouse heart failure model treated with the terpenoid compound I; A in the figure is the calculation result of the ejection fraction (EF), and B in the figure is the calculation result of the fractional shortening (FS); in the figure, "#" indicates P < 0.05; "*" indicates P < 0.05; "**" indicates P < 0.01; "***" indicates P < 0.001.

[0054] Figure 3 HE staining images of heart sections of the mouse heart failure model induced by doxorubicin and the mouse heart failure model treated with the terpenoid compound I, with a scale bar of 100 μm.

[0055] Figure 4 Masson staining images of heart sections of the mouse heart failure model induced by doxorubicin and the mouse heart failure model treated with the terpenoid compound I, with a scale bar of 50 μm.

[0056] Figure 5 These are cardiac ultrasound images of a mouse heart failure model induced by ligation of the left anterior descending coronary artery and a mouse heart failure model treated with the terpenoid compound I.

[0057] Figure 6 The results of cardiac function test of the mouse heart failure model induced by left anterior descending coronary artery ligation and the mouse heart failure model treated with the terpenoid compound I; A in the figure is the calculation result of ejection fraction (EF), and B in the figure is the calculation result of fractional shortening (FS); in the figure, "###" indicates P < 0.001; "***" indicates P < 0.001.

[0058] Figure 7 HE staining images of heart sections of the mouse heart failure model induced by left anterior descending coronary artery ligation and the mouse heart failure model treated with the terpenoid compound I, with a scale bar of 50 μm. DETAILED DESCRIPTION

[0059] The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0060] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0061] Example 1 Obtaining terpenoid compound I from marine fungi

[0062] The heteroterpenoid compound I of the present invention is separated and purified from the fermentation culture of the marine fungus Aspergillus terreus GZU-311. The marine fungus Aspergillus terreus GZU-311 has been deposited in the Guangdong Provincial Microbiological Culture Collection Center on December 17, 2019, with a deposit number of GDMCC No: 60789, and the deposit address is Guangdong Institute of Microbiology, 5th Floor, Building 59, No. 100 Xianlie Middle Road, Guangzhou. The relevant separation and identification information has been disclosed in the patent application with publication number CN111139188A.

[0063] The separation, purification and identification process of the heteroterpenoid compound I is as follows:

[0064] 1. Separation of compounds

[0065] The method for isolating the compound comprises the following steps:

[0066] (1) The marine fungus Aspergillus terreus GZU-311 was inoculated into a slant culture medium (the formula of the slant culture medium was: by mass ratio, 0.3% glucose, 0.1% yeast extract, 0.5% peptone, 2.5% agar, 3% sodium chloride, and water to 100%), and then inoculated into a liquid culture medium (the formula was the same as that of the slant culture medium, except that it did not contain agar), and cultured at 30° C. for 6 days to obtain a seed solution;

[0067] (2) inoculating the seed liquid into a solid corn culture medium (the formula of the solid corn culture medium is: corn: seawater = 1:1, calculated by mass ratio), and leaving it at 30° C. for 60 days to obtain a fermentation culture (fermentation stock solution);

[0068] (3) extracting the fermentation culture with methanol three times, concentrating the extract into a paste, and extracting the obtained concentrated extract with ethyl acetate to obtain a crude ethyl acetate extract;

[0069] (4) The crude ethyl acetate extract was separated by normal phase silica gel chromatography, and then gradient eluted with a petroleum ether / ethyl acetate mixed solution with a volume fraction of 10%, 20%, 30%, 40%, 50%, 60%, and 70% of petroleum ether, respectively, and the 40% petroleum ether / ethyl acetate eluate was collected, and then separated and purified by silica gel, gel and C-18 reverse phase column chromatography separation technology, and the separated and purified compounds were identified;

[0070] 2. Identification of compounds

[0071] The structural analysis of the above separated and purified compounds was performed using high-resolution mass spectrometry and nuclear magnetic resonance (NMR), and the following experimental data were obtained:

[0072] Molecular formula of the compound: C 26 H 32 O9, high resolution mass spectrometry (HRESI-MS): 487.1959 [MH] - (cald forC 26 H 31 O9 487.19626).

[0073] The structural formula of the compound is shown below (Formula (I)):

[0074]

[0075] The NMR data of the compounds are shown in Table 1.

[0076] Table 1 NMR data (CDCl3, 400MHz / 100MHz, ppm)

[0077]

[0078]

[0079] After identification, the compound obtained by separation and purification is a terpenoid compound, which is named as terpenoid compound I.

[0080] Example 2 Effect of heteroterpenoid compound I in the treatment of heart failure induced by doxorubicin

[0081] 1. Experimental methods

[0082] Eight-week-old C57BL / 6 male mice were randomly divided into 6 groups (8 mice in each group): control group (Control), model group (Model), low-dose group of terpenoid I (10 mg / kg)), medium-dose group of terpenoid I (200 mg / kg)), high-dose group of terpenoid I (40 mg / kg) and positive drug saclizumab desvalsartan group (XST).

[0083] The daily oral administration doses are as follows: terpenoid compound I (dissolved in 10% DMSO + saline) at 10, 20, and 40 mg / kg doses; positive drug XST (40 mg / kg); the control group and model group were given an equal amount of blank solvent (10% DMSO + saline). At the same time, doxorubicin was subcutaneously injected once a week, with a single dose of 5 mg / kg, and the control group was injected with an equal amount of saline. The specific oral administration dose is set according to the weight of the mouse, for example, "10 mg / kg" means that a mouse weighing 1 kg is given 10 mg of the drug.

[0084] On the 29th day after oral administration, the cardiac structure and function of mice in each group were evaluated by VINNO 6 small animal high-resolution micro-ultrasound imaging system, and the ejection fraction (EF) and fractional shortening (FS) were calculated. Then, the mice were dissected and the heart embedded sections were obtained for HE staining and Masson staining.

[0085] 2. Data processing

[0086] The experimental results were statistically analyzed using GraphPad Prism 8.0 software and expressed as Mean ± SEM. One-way ANOVA was used for comparison among groups.

[0087] 3. Experimental results

[0088] (1) Cardiac function evaluation

[0089] The cardiac ultrasound images of the mouse heart failure model induced by adriamycin and the mouse heart failure model treated with the terpenoid compound I are shown in FIG. Figure 1 As shown; the cardiac function test results of the mouse heart failure model induced by doxorubicin and the mouse heart failure model treated with the terpenoid compound I are shown Figure 2 As shown. Figure 1 and Figure 2 It can be seen that compared with the control group, the cardiac ejection fraction (EF) and short-axis shortening rate (FS) of the model group mice were significantly decreased, and the left ventricular end-systolic volume and end-diastolic volume were significantly increased, that is, the cardiac function of the mice induced by adriamycin was significantly reduced. Compared with the model group, the cardiac ejection fraction and short-axis shortening rate of the mice treated with terpenoid compound I were significantly increased, and the left ventricular end-systolic volume and end-diastolic volume were reduced, which can significantly improve the cardiac function of the mice induced by adriamycin.

[0090] (2) HE staining of heart sections

[0091] HE staining images of heart sections of the mouse heart failure model induced by adriamycin and the mouse heart failure model treated with the heteroterpenoid compound I are shown in Figure 3 As shown. Figure 3 It can be seen that compared with the control group, the myocardial cells of the mice in the model group were significantly damaged, while the heart sections of the mice treated with 40 mg / kg dose of terpenoid compound I showed little or no myocardial cell damage, and the cells were arranged regularly and densely. This indicates that the terpenoid compound I can reduce the damage of myocardial cells and has a certain protective effect on heart tissue.

[0092] (3) Masson staining of heart sections

[0093] Masson staining of heart sections of the mouse heart failure model induced by adriamycin and the mouse heart failure model treated with the terpenoid compound I are shown in the figure below. Figure 4 As shown. Figure 4 It can be seen that only a small amount of connective tissue thickening was seen in the control group, while there was an obvious large area of ​​connective tissue thickening in the slices of the model group; compared with the model group, treatment with 40 mg / kg dose of terpenoid compound I can significantly reduce doxorubicin-induced connective tissue thickening.

[0094] Example 3 Effect of heteroterpenoid compound I on ischemic heart failure induced by left anterior descending coronary artery ligation

[0095] 1. Experimental methods

[0096] (1) Experimental Materials

[0097] Eight-week-old C57BL / 6 male mice were purchased from Guangdong Zhiyuan Biopharmaceutical Technology Co., Ltd. and were fed with standard feed and had free access to water and food.

[0098] (2) Experimental modeling

[0099] Modeling was performed by ligating the left anterior descending coronary artery (LAD) in situ by thoracotomy. First, mice were anesthetized by intraperitoneal injection of 0.25% sodium pentobarbital, and a ventilator tube was inserted. The ventilator parameters were as follows: tidal volume 11cc, respiratory ratio 1:2, respiratory rate 144 times / min, and the wound was covered with saline gauze; a 1cm incision was made between the 3rd and 4th ribs on the left side of the sternum, and two spreaders were used to open the heart with the ribs up and down, left and right, and the heart was exposed. The pericardium was picked up, and modern standard coded 6-0 silk thread and round needle were used. The needle was inserted at the bifurcation of the left coronary artery and the posterior descending branch 3 to 4mm below the left atrial appendage, with a depth of about 1mm and a width of about 2mm. After the needle was inserted, the ligature was tightened, and the electrocardiogram was observed immediately. If ST segment elevation or wide QRS wave appeared, the chest was sutured and closed; after 4 weeks of feeding after surgery, small animal color Doppler ultrasound was performed to detect cardiac function, and the model was successful when EF was less than 45%.

[0100] (3) Experimental grouping and data determination

[0101] The experimental mice were divided into the following 4 groups (5 mice in each group): blank control group (sutured after thoracotomy without coronary artery ligation, Sham), model group (CHF), model group + terpenoid compound I group (I (20 mg / kg)) and model group + sacubitril valsartan group (XST).

[0102] The dosage of oral administration is as follows: the model group + terpenoid compound I group (dissolved in 10% DMSO + saline) is administered at 20 mg / kg; the model group + sacubitril valsartan group is administered at 26 mg / kg; the blank control group and the model group are given an equal amount of solvent (10% DMSO + saline). The specific oral administration dosage is set according to the weight of the mouse, for example, "20 mg / kg" means that a mouse weighing 1 kg is given 20 mg; oral administration is performed once a day for a total of 4 weeks.

[0103] On the 29th day after intragastric administration, the cardiac structure and function of mice in each group were evaluated by VINNO 6 small animal high-resolution micro-ultrasound imaging system, and the ejection fraction (EF) and fractional shortening (FS) were calculated. Then, the mice were dissected and the heart embedded sections were obtained for HE staining.

[0104] 2. Data processing

[0105] The experimental data were statistically analyzed using GraphPad Prism 8.0 software. The experimental results were expressed as Mean ± SEM, and one-way ANOVA was used for comparison among groups.

[0106] 3. Experimental results

[0107] (1) Cardiac function evaluation

[0108] The cardiac ultrasound images of the mouse heart failure model induced by ligation of the left anterior descending coronary artery and the mouse heart failure model treated with the terpenoid compound I are shown in FIG. Figure 5 As shown; the cardiac function test results of the mouse heart failure model induced by left anterior descending coronary artery ligation and the mouse heart failure model treated with the terpenoid compound I are shown as follows Figure 6 As shown. Figure 6 It can be seen that compared with the blank control group, the cardiac ejection fraction (EF) and short-axis shortening rate (FS) of the mice in the model group were significantly decreased, and the cardiac function of the mice in the model group was significantly reduced; compared with the model group, after treatment with a dose of 20 mg / kg of terpenoid compound I, the EF and FS values ​​of the heart failure model induced by ligation of the left anterior descending coronary artery can be significantly increased, and the cardiac function of mice with heart failure can be improved.

[0109] (2) HE staining of heart sections

[0110] HE staining images of heart sections of the mouse heart failure model induced by left anterior descending coronary artery ligation and the mouse heart failure model treated with the terpenoid compound I are shown in FIG. Figure 7 As shown. Figure 7 It can be seen that compared with the control group, the cardiomyocytes in the model group were arranged in a disorderly manner and inflammatory cells infiltrated in large quantities; compared with the model group, after treatment with 20 mg / kg dose of terpenoid compound I, the infiltration of inflammatory cells can be significantly reduced and the arrangement of cardiomyocytes can be maintained.

[0111] The above results show that the heteroterpenoid compound I of the present invention has an anti-heart failure effect, can be used to prepare anti-heart failure drugs, and has good clinical application prospects.

[0112] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. The use of a terpenoid compound I in the preparation of an anti-heart failure drug, characterized in that: The structural formula of the heteroterpenoid compound I is shown in formula (I):

2. The use according to claim 1, characterized in that: The heteroterpenoid compound I is separated and purified from the fermentation culture of the marine fungus Aspergillus terreus GZU-311; the culture medium used for the fermentation culture is a culture medium prepared from corn and seawater.

3. The application according to claim 1, characterized in that: The heteroterpenoid compound I can improve cardiac function.

4. The use according to claim 3, characterized in that: The heteroterpenoid compound I can improve cardiac ejection fraction and short-axis shortening rate.

5. The use according to claim 1, characterized in that: The heteroterpenoid compound I can reduce myocardial cell damage.

6. The use according to claim 1, characterized in that: The heteroterpenoid compound I can inhibit the thickening of myocardial connective tissue.

7. The use according to claim 1, characterized in that: The terpenoid compound I can improve the disordered arrangement of myocardial cells.

8. The use according to claim 1, characterized in that: The heteroterpenoid compound I can reduce inflammatory cell infiltration.

9. A drug for treating heart failure, characterized in that: Contains the heteroterpenoid compound I described in claim 1 or a pharmaceutically acceptable salt thereof.

10. The drug according to claim 9, characterized in that: It also contains pharmaceutically acceptable excipients.

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