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Application of HIF-1 alpha degradation inhibitor in preparation of drug for coronary heart disease with increased ketone body level

A degradation inhibitor, HIF-1 technology, applied in the field of medicine, can solve the problems of unclear pathways of metabolic changes and few studies on ischemia

Pending Publication Date: 2021-05-04
ZHONGSHAN HOSPITAL FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the pathway of metabolic changes in ischemic and hypoxic myocardium is still unclear, and there are few studies on how to improve ischemic and hypoxic myocardial injury by intervening in metabolic regulation

Method used

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  • Application of HIF-1 alpha degradation inhibitor in preparation of drug for coronary heart disease with increased ketone body level
  • Application of HIF-1 alpha degradation inhibitor in preparation of drug for coronary heart disease with increased ketone body level
  • Application of HIF-1 alpha degradation inhibitor in preparation of drug for coronary heart disease with increased ketone body level

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Elevating β-hydroxybutyric acid levels leads to increased cell death in hypoxic cardiomyocytes.

[0029] Such as figure 1 As shown, it is clear that β-hydroxybutyric acid aggravates hypoxic injury of cardiomyocytes by inhibiting HIF-1α, among which, figure 1 A. figure 1 B shows: the Live / Death junction shows that primary rat cardiomyocytes, after being given β-hydroxybutyric acid under hypoxic conditions, lead to cell death in a dose-dependent manner; figure 1 C shows: Western results show that after administration of β-hydroxybutyric acid, the expression of HIF-1α in hypoxic cardiomyocytes is down-regulated in a dose-dependent manner.

Embodiment 2

[0030] Example 2: Taking HIF-1α as the intervention target can alleviate hypoxic cardiomyocyte injury caused by high β-hydroxybutyric acid.

[0031] Such as figure 2 As shown, using the primary adult mouse cardiomyocytes and human ventricular myocytes, after hypoxic stimulation and β-hydroxybutyric acid, the HIF-1α degradation inhibitor roxadustat was used to up-regulate the expression of HIF-1α, which can Partially reversed β-hydroxybutyric acid-induced cardiomyocyte injury under hypoxic conditions; specifically, figure 2 A and 2B show that the results of Western Blot and immunofluorescence show that after hypoxia stimulation and β-hydroxybutyrate, the application of roxadustat can inhibit the degradation of HIF-1α, and then partially reverse the effect of β-hydroxybutyrate on HIF-1α. inhibitory effect; figure 2 C is the statistical analysis diagram of immunofluorescence results, which can also reflect the experimental results.

Embodiment 3

[0032] Example 3: Elevated levels of ketone bodies in the systemic circulation aggravated myocardial injury in mice with myocardial infarction, and roxadustat partially reversed this effect.

[0033] Animal level experiments: 60 male C57BL / 6 mice aged 6-8 weeks were used, 30 were given a normal diet, and 30 were given a ketogenic diet to establish a hyperketone mouse model. The animal model of myocardial infarction was established by ligation of the descending artery. One week after myocardial infarction, echocardiography was performed, and heart samples were collected for TTC, HE, and Masson staining to identify the myocardial infarction from pathology and morphology. Such as image 3As shown, the expression of HIF-1α was detected by Western-Blot and RT-PCR experiments, and it was found that compared with mice given a normal diet, increasing the level of ketone bodies in the blood can increase the size of myocardial infarction in mice and aggravate myocardial damage. Among th...

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Abstract

The invention discloses application of an HIF-1 alpha degradation inhibitor roxostat in preparation of a drug for coronary heart disease with increased ketone body level. HIF-1 alpha is taken as a target spot, the roxostat is clinically applied to inhibit HIF-1 alpha degradation and increase the HIF-1 alpha level, and myocardial ischemia and hypoxia injury mediated by increase of the ketone body level can be improved. The roxostat is clinically applied to treatment of ischemic heart disease, especially to patients with coronary heart disease with increased blood ketone body level, so as to reduce myocardial cell injury.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the application of HIF-1α degradation inhibitors in the preparation of coronary heart disease drugs with elevated ketone body levels. Background technique [0002] According to the "China Cardiovascular Disease Report 2018", the death caused by cardiovascular disease ranks first in the proportion of deaths among Chinese residents. Myocardial ischemia (myocardialischemia) refers to a pathological state in which cardiac blood perfusion is reduced due to various reasons, resulting in reduced oxygen supply to the heart, abnormal myocardial energy metabolism, and difficulty in maintaining the normal work of the heart. The energy required for heart activity is almost entirely provided by aerobic metabolism, so even in a resting state, the blood oxygen uptake rate of the myocardium is also high. Under normal circumstances, the body can promote a relatively constant blood supply and dem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/472A61P9/10
CPCA61K31/472A61P9/10
Inventor 孙爱军葛均波马秀瑞董震
Owner ZHONGSHAN HOSPITAL FUDAN UNIV
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