Drug for treating heart failure and protecting cardiac functionality

A heart function and drug technology, applied in the field of biomedicine, can solve problems such as heart failure and severe heart failure, and achieve remarkable effects of heart function protection and technological progress

Inactive Publication Date: 2017-08-11
SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the above-mentioned technical problems in the prior art, the present invention provides a drug for treating heart failure and protecting cardiac function. The drug for treating heart failure and protecting cardiac function should solve the problem of GPCR activation in the heart. Induction of technical problems leading to severe heart failure

Method used

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  • Drug for treating heart failure and protecting cardiac functionality
  • Drug for treating heart failure and protecting cardiac functionality
  • Drug for treating heart failure and protecting cardiac functionality

Examples

Experimental program
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Effect test

Embodiment 1

[0024] There are more than 800 members of the GPCRs family. When the GPCR receptor recognizes and binds to the corresponding ligand, it will induce a conformational change, and mainly activate the Gα subunit subfamily (composed of Gαs, Gαi, Gαq, and Gα12 / 13) in the Gαβγ heterotrimer, so that the extracellular The signal is converted into an intracellular signal. Both LRP5 and LRP6 receptors belong to the low-density lipoprotein receptor family, both of which are very similar in structure and function and participate in the activation of Wnt signaling pathway. Therefore two receptors are usually studied together (ie LRP5 / 6). In order to verify the functional impact of LRP5 / 6 receptors on GPCR receptors, the present invention first selects a representative GPCR receptor that plays an important role in heart function: β-adrenoceptor (βAR). The results of co-immunoprecipitation showed that LRP6 receptor and βAR receptor can exist in the same protein complex ( figure 1 ).

[00...

Embodiment 2

[0027] In the in vitro cell experiment, AD-293 cells were co-transfected with LRP6 plasmid and βAR receptor plasmid, and the effect of LRP6 on the activity of downstream signaling pathway of βAR receptor was detected. Luciferase dual-reporter analysis revealed that CRE-luciferase ( c AMP r esponse e lement) as a detection indicator, LRP6 can inhibit the CRE response activated by Iso-βAR ( figure 2 A). Kinetic analysis of cAMP showed that gradient overexpression of LRP6 receptor could dose-dependently inhibit intracellular transient cAMP production mediated by Iso-βAR ( figure 2 B).

[0028] In order to further verify the effect of LRP5 / 6 receptors on the expression of GPCR receptors, siRNA technology was used to knock out LRP5 / 6 in cardiac cardiomyocytes in vitro, and the results showed that the mRNA expression levels of many GPCRs were affected.

Embodiment 3

[0030] Since the binding site of LRP6 and βARs is in the extracellular domain of LRP6, the extracellular domain of LRP6 consists of four β-helix / epidermal growth factor (EGF) repeats (named E1, E2, E3, E4 domains) and three LDL repeats (named LDLR domains). A plasmid expressing the extracellular domain of secreted human LRP6 was constructed and the protein (LRP6N) was purified by querying its nucleic acid sequence from the UniProt database.

[0031] The whole experimental process is as follows: design primers containing BamHI restriction site, capture humanLRP6 extracellular fragment (1-1370AA) (gene nucleic acid sequence as shown in SEQ ID NO.1) cDNA by PCR method, BamHI restriction PCR The product and the linearized pcDNA3.1-6myc vector were purified and ligated with T4 ligase, transformed, coated with resistance plates, single clones were selected, and the insertion direction was verified by PCR and sequenced.

[0032] The constructed plasmid was used to construct hLRP6N-6...

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Abstract

The invention provides application of LRP5 (low-density lipoprotein receptor-related protein 5) or LRP6 in the preparation of drugs for treating heart failure and protecting cardiac functionality, also provides application of LRP6 extracellular domain protein in the preparation of drugs for treating heart failure and protecting cardiac functionality, and also provides a protein, an amino acid sequence of which is shown as in SEQ ID NO. 2. It is analyzed for the first time herein that LRP6 receptor and GPCR (G protein coupled receptor) interact by means of direct binding and that the LRP6 receptor may affect the activity of GPCR by means of direct binding with the same, while what the LRP6 is mainly bound to is its extracellular domain that functions in inhibition. The GPCR receptor engages in massive physiological and pathological processes, especially heart failure, and therefore, the LRP6 extracellular domain protein can truly inhibit GPCR to protect the heart.

Description

technical field [0001] The invention belongs to the field of biomedicine, in particular to a medicine for treating heart failure and protecting heart function. [0002] Background technique: [0003] The canonical Wnt signaling pathway is jointly initiated by the Wnt receptor Frizzled on the plasma membrane and its co-receptor LRP5 / 6. The formation of the LRP5 / 6-Frizzled complex induced by Wnt ligand binding to the receptor is required for activation of the Wnt / β-catenin pathway. The co-receptor of Wnt signaling pathway, low-density lipoprotein receptor-related protein 5 / 6 (LRP5 / 6), belongs to the low-density lipoprotein receptor family. LRP5 / 6 is a type I transmembrane protein, and it has been reported that LRP5 / 6 can directly bind to Frizzled and inhibit the function of Frizzled. Frizzled is a member of the GPCR family, but there are limited reports on the direct relationship between LRP5 / 6 and other GPCR family members and their physiological significance. [0004] The ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61P9/04
CPCA61K38/1709
Inventor 朱伟东
Owner SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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