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CN-121987795-A - Application of IP6K1 or PAS-A as target spot in preparation of medicine for treating and/or preventing myocardial infarction

CN121987795ACN 121987795 ACN121987795 ACN 121987795ACN-121987795-A

Abstract

The invention discloses application of an IP6K1 gene, an IP6K1 protein and A PAS-A protein fragment in screening, preparing A medicament for preventing and/or treating myocardial infarction diseases or improving myocardial cell injury caused by hypoxiA. According to the invention, the direct combination of the IP6K1 protein and PAS-A subdomain of HIF-1 alphA is discovered for the first time through research, so that the degradation of the HIF-1 alphA, the formation of an HIF-1 alphA/ARNT dimer and the combination of the HIF-1 alphA and p53 are influenced, the repair of myocardial cell injury caused by hypoxiA by the HIF-1 alphA and the increase of cell death are limited, and the influence caused by myocardial infarction is further increased. When the IP6K1 gene is knocked out, or the expression of the IP6K1 gene is inhibited, or the IP6K1 protein is degraded, or the expression of the subdomain PAS-A protein fragment of the HIF-1 alphA is increased, the combination of the IP6K1 protein and the HIF-1 alphA can be eliminated, so that the forward action of the HIF-1 alphA is improved, the repair of myocardial cell injury is improved, the cell survival is promoted, and the adverse effect caused by myocardial infarction is reduced.

Inventors

  • Fu Chenglai
  • CHEN YUANYUAN
  • XUE CHUNYAN

Assignees

  • 上海交通大学医学院附属新华医院

Dates

Publication Date
20260508
Application Date
20260212

Claims (10)

  1. The application of the IP6K1 gene as a target spot in screening and preparing medicaments for preventing and/or treating myocardial infarction diseases is characterized in that the medicaments are IP6K1 gene expression inhibitors.
  2. The application of the IP6K1 gene as a target spot in screening and preparing a medicament for improving myocardial cell injury caused by hypoxia, which is characterized in that the medicament is an IP6K1 gene expression inhibitor.
  3. The application of the IP6K1 protein as a target in screening and preparing a medicament for preventing and/or treating myocardial infarction diseases is characterized in that the medicament is an IP6K1 protein degradation agent.
  4. The application of the IP6K1 protein as a target in screening and preparing a medicament for improving myocardial cell injury caused by hypoxia, which is characterized in that the medicament is an IP6K1 protein degradation agent.
  5. Application of IP6K1 gene expression inhibitor or IP6K1 protein degradation agent in preparing medicine for preventing and/or treating myocardial infarction.
  6. Application of IP6K1 gene expression inhibitor or IP6K1 protein degradation agent in preparing medicine for improving myocardial cell injury caused by hypoxia.
  7. Use of A PAS-A protein fragment in the screening, manufacture of A medicament for the prevention and/or treatment of myocardial infarction disorders, wherein said PAS-A protein is A domain in HIF-1A.
  8. 8. Use of A nucleic acid or A viral vector expressing A PAS-A protein fragment for the screening, preparation of A medicament for the prevention and/or treatment of myocardial infarction disorders, wherein the PAS-A protein is A domain in HIF-1A.
  9. Use of A PAS-A protein fragment in the screening and preparation of A medicament for ameliorating myocardial cell damage caused by hypoxiA, wherein said PAS-A protein is A domain in HIF-1A.
  10. 10. Use of A nucleic acid or viral vector expressing A PAS-A protein fragment for the selection and preparation of A medicament for the pre-amelioration of myocardial cell damage caused by hypoxiA, wherein said PAS-A protein is A domain in HIF-1A.

Description

Application of IP6K1 or PAS-A as target spot in preparation of medicine for treating and/or preventing myocardial infarction Technical Field The invention relates to the technical field of biotechnology and medicine, in particular to application of IP6K1 or PAS-A serving as A target point in preparing A medicine for treating and/or preventing myocardial infarction. Background Myocardial infarction is a leading cause of death. Hypoxia is the major pathological cause of cell death. Ischemia and hypoxia cause upregulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha), HIF-1 alpha plays a complex role in determining cell fate. HIF-1 a initiates metabolic reprogramming, which is critical for early adaptation to hypoxic environments. However, outside the early adaptation phase, accumulated HIF-1 a is involved in hypoxia-induced cell death. The p53 pathway plays a key role in mediating hypoxia-induced cell death. HIF-1α can bind to p53, leading to activation of the p53 pathway and subsequent cell death. Therefore, HIF-1α exhibits a dual and opposite role in response to hypoxic conditions, on the one hand, it promotes cell survival by forming an active transcriptional complex with aromatic nuclear receptor transporter (ARNT, also known as HIF-1β) and, on the other hand, it induces cell death by binding to p 53. Importantly, HIF-1α, which does not bind ARNT, can bind to p 53. Thus, myocardial infarction injury may be alleviated by balancing hypoxia signals by enhancing HIF-1α/arnt-mediated adaptive responses, while reducing HIF-1α/p 53-mediated cell death. Potential strategies to achieve this balance include targeting specific HIF-1α interactions to support survival rather than death signaling. HIF-1 a is constantly transcribed, but its protein levels are regulated primarily by degradation mediated by the oxygen-dependent ubiquitin-proteasome pathway. An oxygen activated Proline Hydroxylase Domain (PHD) protein that hydroxylates HIF-1 alpha at a specific proline residue. This hydroxylation enables von Hippel-Lindau protein (pVHL), which is a component of the E3 ubiquitin ligase complex, to recognize HIF-1α. HIF-1 a is then ubiquitinated and degraded by the proteasome. Therefore, only trace amounts of HIF-1. Alpha. Protein can be detected under physiological conditions. In contrast, under hypoxic conditions, PHD activity is impaired, resulting in the accumulation of HIF-1. Alpha. HIF-1 a binds to ARNT to form the active transcription factor HIF-1, activating gene expression, coordinating the cellular response to ischemia/hypoxia. However, HIF-1α, which does not form heterodimers with ARNT, can bind p53, thereby promoting p 53-dependent cell death. Specific deletion of PHD enzymes or pVHL by cardiomyocytes results in prolonged HIF-1 alpha expression, leading to degenerative changes in the heart. Likewise, heart-specific HIF-1 a transgenic mice exhibit stable decline in cardiac function and acceleration of cardiac dysfunction in both transected aortic contraction and aged cardiomyopathy models. Therefore, precise regulation of HIF-1 a is critical to balance the hypoxia response. Inositol phosphates are intracellular signaling molecules, inositol-1, 3,4,5, 6-pentaphosphate (InsP 5) has been shown to enhance phd-dependent HIF-1α degradation. InsP5 is further phosphorylated to inositol 5-bisphosphate 1,2,3,4,6-pentakisphosphate (5 PP-InsP 5), the most abundant inositol pyrophosphate involved in regulating a variety of cellular processes such as protein stability. Phytase 1 (IP 6K 1) is the main kinase in mammalian cells which produces up to 70% of 5PP-InsP 5. IP6K1 and 5PP-InsP5 are involved in mediating age-related diseases including endothelial dysfunction and nonalcoholic fatty liver disease. Preclinical studies have shown that inhibition of IP6K1 enhances the biosynthesis of cardiovascular protective factors, including adiponectin and High Density Lipoprotein (HDL). Disclosure of Invention The invention aims to provide an application of an IP6K1 gene serving as a target spot in screening and preparing a medicament for preventing and/or treating myocardial infarction diseases, wherein the medicament is an IP6K1 gene expression inhibitor. According to the invention, the direct combination of the IP6K1 protein and PAS-A subdomain of HIF-1 alphA is discovered for the first time through research, so that the degradation of the HIF-1 alphA, the formation of an HIF-1 alphA/ARNT dimer and the combination of the HIF-1 alphA and p53 are influenced, the repair of myocardial cell injury caused by hypoxiA by the HIF-1 alphA and the increase of cell death are limited, and the influence caused by myocardial infarction is further increased. When the IP6K1 gene is knocked out, or the expression of the IP6K1 gene is inhibited, or the IP6K1 protein is degraded, or the PAS-A protein fragment expression is increased, the combination of the IP6K1 protein and HIF-1 alphA can be eliminated, so that the forward action of the HIF-1 alphA i