CN116650457B - Application of PDK1 inhibitor DCA in treatment of aortic aneurysm and dissection - Google Patents

Abstract

The invention discloses application of a PDK1 inhibitor DCA in treating aortic aneurysm and dissection. The invention uses an AngII-induced aortic aneurysm mouse model, and detects the therapeutic effect of DCA on aortic dissection of heart aortic aneurysm through indexes of survival rate, aortic aneurysm incidence rate, aortic width, vascular staining and WB staining, thereby providing a new target and medicament for clinically treating aortic dissection of aortic aneurysm. The DCA of the PDK1 inhibitor provided by the invention is a brand-new drug treatment means for treating aortic aneurysm and interlayer, is an important supplement to the operation for treating aortic aneurysm/interlayer, can slow down the occurrence and progress of aortic aneurysm, reduces the occurrence of aortic basal layer, and has important clinical significance.

Description

The use of PDK1 inhibitor DCA in the treatment of aortic aneurysms and dissections

Technical field

The present invention relates to the application of PDK1 inhibitor DCA in the treatment of aortic aneurysm and dissection, and belongs to the field of biomedical technology.

Background technique

Aortic aneurysm/dissection (AA/AD) is a clinical emergency with high morbidity and mortality. AD occurs when the inner layer of the aortic wall (intima) ruptures and blood enters the aortic media through the tear. The global prevalence of AD is 1.3%-8%. An epidemiological study based on the China Urban Employees Basic Medical Insurance (UEBMI) database estimated the annual incidence of AD to be 2.78/100,000 people. The mortality rate caused by AD rupture is approximately 90%, causing an annual economic burden of more than 10 billion yuan in China alone. Early screening of high-risk groups (high risk factors for hypertension, etc.) has been proven to be an effective method to prevent AD-related deaths. Early diagnosis and screening of AD are particularly necessary. Although emergency surgery can be performed in AD patients with large vessel diameters, rapid growth, or symptoms, postoperative mortality remains around 50%. Despite this, there are currently no effective drugs that can prevent the occurrence of AD or reverse the progression of AD. Aortic interventional therapy or open surgery is still the first choice for the treatment of AD. Therefore, it is crucial to explore potential therapeutic targets for AD.

Cells decompose glucose into synthetic intermediates of biological macromolecules through the glycolysis pathway by inhibiting the activity of pyruvate dehydrogenase complex (PDC) in mitochondria. In this process, pyruvate dehydrogenase kinases (PDKs) play a key role. Inhibiting PDK1 activity in cells can effectively block this metabolic pathway, while also activating mitochondrial oxidative metabolism and inducing apoptosis. Currently, there are no relevant reports on the therapeutic effect of PDK1-specific inhibitors on aortic aneurysms/dissections.

Contents of the invention

The purpose of the present invention is to solve the problem that currently there is no good drug treatment method to treat aortic aneurysm/dissection except for surgical intervention; the purpose of the present invention is to provide the PDK1 inhibitor DCA in the preparation of drugs for the treatment of aortic aneurysm and dissection. Application: The present invention proves through animal experiments that the PDK1 inhibitor DCA can effectively reduce the formation and development of aortic aneurysms, reduce the occurrence of aortic dissection, and provides new targets and drugs for the clinical treatment of aortic aneurysms.

In order to achieve the purpose of solving the above problems, the technical solution adopted by the present invention is to provide the application of PDK1 inhibitor dichloroacetic acid or its derivatives in the preparation of drugs for the treatment of aortic aneurysms and dissections.

Preferably, the dichloroacetic acid derivative is a salt or esterification product of dichloroacetic acid.

Preferably, the PDK1 inhibitor is sodium dichloroacetate.

Preferably, the dosage form of the drug includes injection, tablet, powder, suspension, capsule, pill or syrup.

Compared with the prior art, the beneficial effects of the present invention are:

The therapeutic effect of PDK1-specific inhibitors on aortic aneurysms/dissections has not yet been discovered. In the present invention, by administering the PDK1 inhibitor DCA to mice, the PDK1 inhibitors can effectively reduce the occurrence and development of aortic aneurysms and reduce the occurrence of aortic dissections. The clinical treatment of aortic aneurysm/dissection provides new targets and drugs; PDK1 inhibitors can be used as an important supplement to traditional surgical interventional treatments, which can delay the development and progression of aortic aneurysms and reduce the occurrence of adverse events such as death. , has good potential application prospects in clinical practice.

Description of drawings

Figure 1 shows the survival curves of two groups of mice;

Figure 2 shows the aortic tumor formation and vasodilation in mice with aortic aneurysm/dissection treated with DCA drugs;

Figure 3 shows the results of HE and EVG staining of blood vessel sections of mice with aortic aneurysm/dissection treated with DCA drugs.

Detailed ways

In order to make the present invention more obvious and understandable, preferred embodiments are described in detail below along with the accompanying drawings.

The test methods used in the following examples are conventional methods unless otherwise stated; the materials and reagents used, unless otherwise stated, are commercially available reagents and materials.

Example

1) Preparation of experimental animals and animal models: SPF grade adult male C57BL/6 mice (8 weeks old, 20-25g) were used. The mice were subcutaneously infused with Ang II (2500ng/kg· min) and 0.9% physiological saline with a penetration volume of 0.5 μl/hr, and continued to pump for 28 days to construct aortic aneurysm and dissection models. They were divided into WT group and WT+DCA (sodium dichloroacetate) drug group. Among them, the drug group used DCA for daily intragastric administration (150 mg/kg). The mouse survival curve was recorded daily. At the end of the modeling, the survival curve showed that the mortality rate (10%) of mice treated with DCA (sodium dichloroacetate) was less than that of the WT group (30%), and there was a statistically significant difference between the two groups. Difference (P=0.02), as shown in Figure 1. After 28 days, the mice were euthanized and the tissue was collected. The embedded tissue was fixed and paraffin sectioned, and H&E staining and EVG staining were performed. The tearing of aortic elastic fibers and the formation of false lumen were observed under a microscope. The experimental protocol was approved by the Animal Care and Ethics Committee of Fudan University.

2) Take samples to observe aortic expansion and tumor formation

To collect blood vessels, open the abdominal cavity and take out the blood vessels, place them in a 10cm petri dish containing pre-cooled PBS buffer on ice, quickly cut off the excess tissue, slightly absorb the excess PBS on the gauze, weigh and record on the balance, be careful to avoid squeezing. Pressure, bruises and dryness. Take pictures with a Leica microscope to leave evidence to observe aortic aneurysm formation and blood vessel dilation. The results showed that the width of the aorta of mice in the drug-treated group was reduced, and the occurrence of aortic aneurysms was reduced (59% in the WT group vs. 41% in the WT+DCA group). There was a statistical difference between the two groups (P<0.05), as shown in Figure 2 .

3) Dyeing

Blood vessel sections from the lesions were taken for HE and EVG staining. The results showed that the degradation of vascular elastin and the disorder of elastic fibers in mice in the DCA drug-treated group were significantly improved compared with the control group. The elastic fiber content was: 37.47±9.62 in the WT+DCA group vs. 19.54±5.09 in the WT group. The difference between the two groups There is a statistical difference (P<0.05), as shown in Figure 3.

The above embodiments are only preferred embodiments of the present invention, and do not limit the present invention in any form or substance. It should be pointed out that those of ordinary skill in the art can also make other modifications without departing from the present invention. There are several improvements and supplements, which should also be considered as the protection scope of the present invention.

Claims (3)

1. Use of the pdk1 inhibitor dichloroacetic acid or its salts for the preparation of a medicament for the treatment of aortic aneurysms.
2. 2. The use of claim 1, wherein the PDK1 inhibitor is sodium dichloroacetate.
3. 3. The use according to claim 1 or 2, wherein the pharmaceutical dosage form comprises an injection, a tablet, a powder, a suspension, a capsule, a pill or a syrup.