CN-120789089-B - Use of SIAH inhibitors for treating heart failure or improving myocardial cell function

Abstract

The invention discloses an application of SIAH inhibitor in treating heart failure or improving myocardial cell function, relates to the technical field of medical treatment, and is used for researching the treatment effect and treatment mechanism of SIAH2 on heart failure. The invention provides an application of SIAH gene or protein inhibitor in preparing heart failure medicines, and utilizes SIAH2 inhibitor to interfere with TAC-induced mouse heart failure model, and discovers that SIAH inhibitor can improve myocardial energy metabolism and protect heart function.

Inventors

• XIAO HAN
• Cui hongtu
• Dong Erdan
• ZHANG YOUYI

Assignees

• 北京大学第三医院（北京大学第三临床医学院）

Dates

Publication Date

20260508

Application Date

20250812

Claims (5)

1. Use of an inhibitor of a siah2 gene or protein for the preparation of a medicament for heart failure, characterized in that the inhibitor acts directly on SIAH gene or protein, the inhibitor being a SIAH gene knockout agent; The SIAH gene knockout reagent is siRNA, the nucleotide sequence of the sense strand of the siRNA is shown as SEQ ID NO. 1, and the nucleotide sequence of the antisense strand of the siRNA is shown as SEQ ID NO. 2.
2. 2. The use according to claim 1, wherein the inhibitor is for inhibiting mRNA expression levels of heart failure heart tissue heart failure markers.
3. 3. The use according to claim 2, wherein the heart failure marker mRNA comprises ANP, BNP, β -MHC, col1a1 and/or col3a1.
4. 4. The use according to claim 1, wherein the inhibitor is for inhibiting a decrease in the expression of a mitochondrial function marker in heart tissue of heart failure.
5. 5. The use according to claim 4, wherein the mitochondrial function marker is Nudfa11, SDHB, uqcrb, cox6a2 and/or ATP5e.

Description

Use of SIAH inhibitors for treating heart failure or improving myocardial cell function Technical Field The invention relates to the technical field of medical treatment, in particular to application of SIAH inhibitor in treating heart failure or improving myocardial cell function. Background The heart is an organ with high energy requirements and must continuously produce ATP to maintain the systolic function of the heart, and the ATP stored in the heart can only maintain the heart for 2-10 seconds of beating. Mitochondrial oxidative metabolism is the primary source of cardiac energy, and the energy supply of healthy hearts is derived from a variety of energy substrates, about 40% -60% from fatty acid oxidation, and 20% -40% from glucose metabolism. In the heart of failure, however, there is a change in energy metabolism, and the ATP content in the heart is reduced by about 30% at the end of heart failure compared to a healthy heart, resulting in an insufficient energy supply and ultimately a myocardial contractile dysfunction. This change in energy metabolism may be due to impaired mitochondrial oxidative metabolism, changes in cardiac energy substrate preference, reduced cardiac efficiency, etc. Metabolic remodeling plays an important role in regulating cardiac energy substrate utilization, ionic and redox homeostasis, maintaining ATP content, etc., and is critical to maintaining cardiac contractile function. And accumulation of part of the metabolites further aggravates metabolic disorders during cardiac metabolic remodeling. However, in the heart failure onset process, the signal paths involved in cardiac metabolic remodeling are quite complex, the regulation mechanism is not clear, and the current research is insufficient. Ubiquitin-proteinase system (UPS) is a key protein degradation pathway in cells responsible for regulating various cellular processes including cell cycle, signaling, gene expression, stress response, and metabolic balance. In recent years, E3 ubiquitin ligase has been increasingly studied in cardiovascular diseases, and through specific recognition of substrate proteins and promotion of ubiquitination degradation or stabilization of the substrate proteins, processes of signal transduction, apoptosis, inflammatory reaction and the like of the cardiovascular system are regulated. E3 ubiquitin ligase plays an important role in cardiovascular diseases, further explores a specific mechanism of the ubiquitin ligase in the occurrence and development of cardiovascular diseases, and has important potential clinical application value as a treatment target. In our study, we performed a combination of beta receptor overactivation (ISO-stimulated) cardiomyocyte transcriptome with mouse heart failure transcriptome and human heart failure transcriptome, found that the ubiquitination-related signaling pathway was significantly enriched in the co-altered genes, and further found that SIAH2 was the more significantly altered E3 ubiquitin ligase by analysis of the differential genes in the ubiquitination pathway. SIAH2 (Seven in Absentia Homolog) is an E3 ubiquitin ligase belonging to the SIAH family (Siah proteins) and the role in various cellular processes has been gradually revealed. It is mainly involved in the processes of cell cycle, transcriptional regulation, metabolic regulation, cell stress reaction and the like by regulating protein ubiquitination. The mechanism of action of SIAH2 and the function in different diseases are being increasingly studied, especially in cardiovascular diseases, cancer, neurodegenerative diseases and metabolic diseases, the role of SIAH2 as a key regulatory factor is becoming more and more clear. For example, SIAH2 mediates ubiquitination degradation of ZFP521 in the adipogenesis process, promotes the formation of fat in fat precursor cells, SIAH can regulate DNA damage repair by promoting CtIP ubiquitination, SIAH can enhance the stability of HIF-1 alpha by degrading PHD2 and PHD3, thereby promoting hypoxia adaptation of cancer cells, enhancing invasion and metastasis capability of cancer cells, and the like. Therefore, SIAH2 has been shown to be closely related to cellular stress, inflammatory response and apoptosis in a variety of disease states based on the above related studies, however the role of SIAH2 in heart failure is not clear. Disclosure of Invention In view of the above analysis, the present invention aims to provide a SIAH inhibitor for use in treating heart failure or improving myocardial cell function, for studying SIAH therapeutic effect on heart failure and therapeutic mechanism. The aim of the invention is mainly realized by the following technical scheme: In one aspect, the invention provides an application of SIAH gene or protein inhibitor in preparing a medicine for treating heart failure. Further, in the application, the inhibitor comprises a specific small molecule inhibitor, wherein the chemical structural formula of the specific small m