Application of deaminotyrosine in preparation of medicine for delaying heart aging and treating and / or preventing senile heart disease

Abstract

The invention discloses application of deaminotyrosine in preparation of a medicine for delaying heart aging and treating and / or preventing senile heart diseases, and belongs to the technical field of medicines. Experiments prove that deaminotyrosine can effectively reduce senescent cell accumulation in senescent hearts and remarkably improve the diastolic function and stress reserve capacity of naturally senescent animals. The application provides a brand-new, effective and high-potential-safety drug treatment strategy for dealing with heart aging and related disease challenges caused by population aging, and has great social and economic values.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, and in particular relates to the use of deaminotyrosine in the preparation of medicaments for delaying cardiac aging and for treating and / or preventing age-related heart disease. Background Technology

[0002] Cardiac aging is one of the most critical aspects of the aging process, characterized by a decrease in the number of cardiomyocytes, myocardial hypertrophy, diastolic dysfunction, reduced maximum cardiac output, and diminished reserve capacity in response to stresses such as ischemia and β-adrenergic stimulation. These changes are the root cause of the increased susceptibility of older adults to heart failure, atrial fibrillation, and other age-related heart diseases, severely impacting their quality of life and life expectancy. Currently, there are no specific drugs in clinical practice that directly slow down the aging process of the heart or target its underlying mechanisms. Treatment primarily focuses on symptom management after end-stage events such as heart failure, lacking effective early intervention strategies.

[0003] The molecular mechanisms of cardiac aging are complex, including cardiomyocyte senescence, mitochondrial dysfunction, accumulation of oxidative stress, impaired autophagic flux, low-grade chronic inflammation, and extracellular matrix fibrosis. Therefore, ideal interventions should target multiple core aspects mentioned above.

[0004] Desaminotyrosine (DAT) is an endogenous aromatic amino acid metabolite. While there are sporadic reports on its anti-inflammatory activity in existing technologies, no literature or technological insights have yet revealed whether DAT can directly intervene in the biological processes of cardiac aging, improve the physiological aging phenotype of the heart, and prevent age-related heart diseases. Therefore, developing a safe and effective drug that targets the core mechanisms of cardiac aging has significant clinical need and market value. Summary of the Invention

[0005] To overcome the aforementioned deficiencies in the prior art, this application provides the use of deaminotyrosine in the preparation of medicaments for delaying cardiac aging and for treating and / or preventing age-related heart disease.

[0006] To achieve the above-mentioned objectives, this application provides the following technical solution: On the one hand, this application provides the use of deaminotyrosine in the preparation of medicaments for delaying cardiac aging and for treating and / or preventing age-related heart disease.

[0007] Optionally, the deaminotyrosine achieves the effect of delaying cardiac aging through at least one of the following pathways: (1) Reduce the accumulation of senescent cells (such as senescent cardiomyocytes and cardiac fibroblasts) in myocardial tissue; (2) Improve the biosynthesis and function of myocardial mitochondria or inhibit oxidative stress damage in cardiac tissue; (3) Enhances the autophagy activity of cardiomyocytes; (4) Reduces age-related cardiac fibrosis and low-grade inflammation.

[0008] Optionally, the age-related heart disease includes at least one of age-related diastolic dysfunction, heart failure with preserved ejection fraction, and age-related atrial fibrillation.

[0009] Optionally, the dosage of the deaminotyrosine is 10-50 mg / day.

[0010] Optionally, the dosage form of the drug includes an oral formulation or an injectable formulation.

[0011] Optionally, the oral formulation includes tablets, capsules, granules, or oral liquid; The injectable formulation includes intravenous injection or intraperitoneal injection.

[0012] Optionally, the drug may also include a pharmaceutically acceptable carrier, diluent, or excipient.

[0013] Secondly, this application provides a pharmaceutical composition for delaying cardiac aging and treating and / or preventing age-related heart disease, wherein the pharmaceutical composition uses deaminotyrosine or its pharmaceutically acceptable salt, ester, solvate or prodrug as the active ingredient.

[0014] Optionally, the pharmaceutical composition may further include a pharmaceutically acceptable carrier, diluent, or excipient.

[0015] Compared with the prior art, this application has the following advantages: (1) Strong targeting: This application is the first to discover and confirm that DAT can specifically intervene in the core biological processes of cardiac aging, filling the technological gap in this field.

[0016] (2) Synergistic effect of multiple mechanisms: This study found that DAT works synergistically through multiple pathways such as clearing senescent cells, protecting mitochondria, reducing oxidative stress and fibrosis, and reversing cardiac aging phenotypes at multiple stages.

[0017] (3) Significant effect: In the naturally aging mouse model, DAT intervention can significantly improve cardiac diastolic function, reduce myocardial stiffness, and enhance stress tolerance, with clear effects.

[0018] (4) Prevention and treatment: The drug provided in this application can not only be used to treat existing age-related heart disease (such as HFpEF), but its more important value lies in the early delay and prevention of the aging process of the heart, thus achieving "prevention of disease".

[0019] (5) Original innovation and high safety: As an endogenous substance, the discovery of new uses for DAT is an original innovation, and it is expected to have extremely high biosafety and good drug-like prospects. Attached Figure Description

[0020] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 This application investigates the effects of DAT on doxorubicin (DOX)-induced senescence-related markers (p21 and p53) and β-galactosidase (SA-β-gal) activity in H9C2 cardiomyocytes (Note: A indicates P21 and P53 protein levels detected by Western blot; B indicates β-galactosidase activity detected by SA-β-gal staining; * indicates p<0.05; ** indicates p<0.01; *** indicates p<0.001). Figure 2 This study investigated the effect of DAT on the expression of aging-related marker proteins in rapidly aging mice (Note: *** indicates p<0.001; **** indicates p<0.0001). Figure 3 This application examines the effect of DAT on diastolic function of the heart in naturally aging mice. Figure 4 The effect of DAT on cardiac systolic function in rapidly aging mice was measured by small animal ultrasound (Note: * indicates p<0.05; ** indicates p<0.01; *** indicates p<0.001). Detailed Implementation

[0022] The present application is further illustrated below with reference to specific embodiments. The following descriptions are merely a few embodiments of the present application and are not intended to limit the present application in any way. Although the present application discloses preferred embodiments as follows, they are not intended to limit the present application. Any modifications or variations made by those skilled in the art without departing from the scope of the technical solution of the present application using the disclosed technical content are equivalent to equivalent implementation cases and all fall within the scope of the technical solution.

[0023] Unless otherwise specified, the raw materials used in the embodiments of this application are all purchased commercially and used directly without any special treatment.

[0024] Unless otherwise specified, the analytical methods in the embodiments all adopt conventional instrument or equipment settings and conventional analytical methods. Example

[0025] Inhibitory effect of DAT on cardiomyocyte senescence A senescence model of H9C2 cardiomyocytes was induced using doxorubicin (DOX), and the cells were treated with different concentrations of DAT. Western blot analysis was used to detect the expression of senescence-related proteins p53 and p21. The results showed that compared with the blank control group, the expression of p53 and p21 was significantly increased in the DOX-treated group, and DAT treatment dose-dependently inhibited the DOX-induced increase in p53 and p21 expression. Figure 1 (A) SA-β-gal staining showed that, compared with the blank control group, the number of SA-β-gal positive cells in the DOX-treated group was significantly increased, and DAT treatment could inhibit the increase in the number of SA-β-gal positive cells induced by DOX ( Figure 1 (B in the middle). Example

[0026] Inhibitory effect of DAT on cardiomyocyte senescence in aging mice A rapid aging model was established using 6-month-old SAMP8 mice. The mice were treated orally with DAT aqueous solution for 3 months. After treatment, heart tissue was collected, and Western blot analysis was performed to detect the expression of aging-related proteins p53 and p16. The results showed that compared to the SAMR1 anti-aging group, the expression levels of p53 and p16 in the SAMP8 aging group were significantly increased. DAT treatment effectively inhibited the aging-induced significant increase in p53 and p16 expression levels. Figure 2 ). Example

[0027] Inhibitory effect of DAT on cardiac remodeling in aging mice Mouse hearts from Example 2 were taken and their size observed. WGA staining was used to detect cardiomyocyte area, and MASSON staining was used to detect fibrosis. Results are as follows: Figure 3 As shown, compared with the SAMR1 anti-aging group, the SAMP8 aging group showed increased heart volume, increased cardiomyocyte area, and significant myocardial fibrosis, while DAT treatment could inhibit the aging-induced increase in heart volume, increased cardiomyocyte area, and myocardial fibrosis. Example

[0028] The enhancing effect of DAT on cardiac contractile function Noninvasive cardiac function assessment was performed on the mice in Example 1 using small animal echocardiography. The analysis focused on LVEF (left ventricular ejection fraction) and LVFS (left ventricular fractional shortening). Results are as follows: Figure 4As shown, compared to the SAMR1 anti-aging group, the SAMP8 aging group showed a significant decrease in LVEF and LVFS levels, while DAT treatment could inhibit the age-related decrease in LVEF and LVFS levels. Figure 4 ).

[0029] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. The use of deaminotyrosine in the preparation of drugs for delaying cardiac aging and for the treatment and / or prevention of age-related heart disease.

2. The application according to claim 1, characterized in that, The deaminotyrosine achieves the effect of delaying cardiac aging through at least one of the following pathways: (1) Reduce the accumulation of senescent cells (such as senescent cardiomyocytes and cardiac fibroblasts) in myocardial tissue; (2) Improve the biosynthesis and function of myocardial mitochondria or inhibit oxidative stress damage in cardiac tissue; (3) Enhances the autophagy activity of cardiomyocytes; (4) Reduces age-related cardiac fibrosis and low-grade inflammation.

3. The application according to claim 1, characterized in that, The aforementioned age-related heart disease includes at least one of age-related diastolic dysfunction, heart failure with preserved ejection fraction, and age-related atrial fibrillation.

4. The application according to claim 1, characterized in that, The dosage of the deaminotyrosine is 10-50 mg / day.

5. The application according to claim 1, characterized in that, The dosage forms of the drug include oral formulations or injectable formulations.

6. The application according to claim 5, characterized in that, The oral preparations include tablets, capsules, granules, or oral liquids; The injectable formulation includes intravenous injection or intraperitoneal injection.

7. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable carriers, diluents, or excipients.

8. A pharmaceutical composition for delaying cardiac aging and treating and / or preventing age-related heart disease, characterized in that, The pharmaceutical composition uses deaminotyrosine or its pharmaceutically acceptable salt, ester, solvate or prodrug as the active ingredient.

9. A pharmaceutical composition according to claim 8 for delaying cardiac aging and treating and / or preventing age-related heart disease, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier, diluent, or excipient.

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