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Application of NADPH oxidase 2 as therapeutic target in preparation of medicine for treating vascular dysfunction

A technology for dysfunctional and oxidative enzymes, applied in the field of biomedicine, can solve problems such as functional impairment

Pending Publication Date: 2022-05-20
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although widely used in clinical practice, many international large-scale clinical studies have shown that the use of rapamycin can lead to impaired arterial endothelial cell-dependent dilatation (EDD) function

Method used

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  • Application of NADPH oxidase 2 as therapeutic target in preparation of medicine for treating vascular dysfunction
  • Application of NADPH oxidase 2 as therapeutic target in preparation of medicine for treating vascular dysfunction
  • Application of NADPH oxidase 2 as therapeutic target in preparation of medicine for treating vascular dysfunction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1, intraperitoneal injection of rapamycin damages mouse aortic EDD function

[0038] C57BL / 6 background mice were randomly divided into control group and treatment group. The mice in the control group were intraperitoneally injected with corn oil, and the mice in the treatment group were injected intraperitoneally with 2 mg / kg body weight of rapamycin, which was similar to the blood concentration achieved by clinical use of rapamycin. After the mice were anesthetized by intraperitoneal injection of 1% pentobarbital sodium (60 mg / kg), they were placed in a supine position, their abdomen was shaved, and couplant was applied. The end-diastolic diameter of the abdominal aorta was detected with an ultrasound instrument (Vevo 770). During the measurement, the ultrasound probe remained at the same position, and the average values ​​of the three cardiac cycles were taken. First, measure the inner diameter of the abdominal aorta (denoted as D 0 ), and then tied the rig...

Embodiment 2

[0039] Example 2. Knocking out the Mtor gene in EC to inhibit mTOR, or the Rictor gene to inhibit mTORC2, both damage the mouse aortic EDD function

[0040] Mtor flox / flox and Cdh5Cre ERT2 After the mice were crossed, the EC-specific Mtor gene knockout mice (Mtor EC- / - ) and its control (WT) mice. Likewise, Rictor flox / flox and Cdh5Cre ERT2 After the mice were crossed, the EC-specific Rictor gene knockout mice (Rictor EC- / - ) and their control mice. Select about 6 weeks Mtor EC- / - and Rictor EC- / - and wild-type mice of the same age and sex, and induced EC-specific gene knockout by intraperitoneal injection of tamoxifen for a week. Transcutaneous ultrasound examination of vasomotor function was the same as above.

[0041] result( figure 2 ) shows that knocking out the Mtor gene in EC to inhibit mTOR, or knocking out Rictor in EC to inhibit mTORC2, both damage the mouse aortic EDD function. %. This suggests that mTORC2 is involved in maintaining normal arterial EDD ...

Embodiment 3

[0042] Example 3. Inhibition of mTOR or mTORC2 significantly reduces the EDD function of isolated vascular rings

[0043] Mtor processed from Example 2 EC- / - or Rictor EC- / - and its control mice to isolate the aortic vascular ring, with 10 -9 ~10 -5 Acetylcholine (Ach) with a mol / L concentration of 10 times as a gradient induced EDD respectively, and was detected by an isolated blood vessel tonometry (Myograph). result( image 3 ) showed that the deletion of mTOR or Rictor in EC significantly reduced the degree of EDD in the aortic vascular ring, which was consistent with the above in vivo experimental results, and further supported the conclusion that the above mTOR-inhibiting drugs inhibited the function of EDD by inhibiting mTORC2.

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Abstract

In order to solve the problem that endothelium-dependent artery vasodilatation function is damaged due to rapamycin drugs, the invention provides application of NADPH oxidase 2 as a therapeutic target in preparation of drugs for treating vascular dysfunction. The invention also provides an application of the substance for inhibiting the gene expression of the NADPH oxidase 2 or the substance for inhibiting the activity of the NADPH oxidase 2 in preparation of drugs for treating vascular dysfunction. The activity of NADPH oxidase 2 or Nox2 gene expression is inhibited, or the activity of EC cell p38 kinase and JNK1 / 2 kinase is inhibited to inhibit the Nox2 gene expression and activity, the level of active oxygen in blood can be reduced, the level of NO can be improved, and the vasodilation function of arterial endothelium dependence damaged by mTORC2 inhibition can be improved, so that the side effects of rapamycin drugs are reduced, the treatment effect is enhanced, and the application prospect is broad. Or is applied to design of novel mTOR inhibiting drugs with better curative effects and lower side effects. The invention also provides an application of the substance for reducing the ROS content in blood and increasing the NO content in blood in preparation of a medicine for treating vascular dysfunction.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to the application of NADPH oxidase 2 as a therapeutic target in the preparation of drugs for treating vascular dysfunction. Background technique [0002] In the world, including in my country, the morbidity and mortality of cardiovascular diseases have ranked first, higher than tumors and other diseases, seriously endangering human health. The most common cardiovascular disease is coronary heart disease, which is a disease caused by atherosclerotic plaques in the coronary arteries (coronary arteries) of the heart, narrowing or blocking the coronary lumen, causing myocardial ischemia, hypoxia or even necrosis . Coronary artery stent implantation, developed at the end of the last century, implants metal stents in narrow coronary artery segments to open the blood vessels and restore blood supply. It is currently the most effective means of treating coronary heart disea...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P9/14
CPCA61K45/00A61P9/14
Inventor 孙崇秀张代民肖平喜
Owner NANJING MEDICAL UNIV
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