CN116531398A - Application of CircRAB3IP in preparation of drugs for treating heart failure - Google Patents
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Abstract
The invention relates to an application of CircRAB3IP in preparing a medicament for treating heart failure, and belongs to the technical field of biological medicines. The invention provides an application of CircRAB3IP in preparing a medicament for preventing or treating heart failure, myocardial fibrosis, myocarditis or promoting lymphatic vessel neogenesis; provides the application of the CircRAB3IP in preparing a heart failure prognosis diagnosis kit. The invention discloses that CircRAB3IP participates in the regulation of lymphatic vessel neogenesis and has a heart protection effect in hypertension heart reconstruction; the invention can effectively improve cardiac dysfunction caused by mechanical stress of hypertension, slow down heart reconstruction and myocardial fibrosis, and reduce heart inflammation; provides a new target point for the treatment of hypertension heart reconstruction.
Description
Technical Field
The invention relates to an application of CircRAB3IP in preparing a medicament for treating heart failure, and belongs to the technical field of biological medicines.
Background
Cardiovascular disease (Cardiovascular disease, CVD) has become the leading cause of death in our country and even worldwide, and the prevalence is still in the rising phase. The sustained mechanical stress stimulation of hypertension can cause structural and functional changes of cardiac muscle or non-cardiac muscle cells, cause poor reconstruction of heart, often appear as damage of cardiac vascular system function, myocardial interstitial fibrosis, myocardial apoptosis and the like, finally cause heart failure and seriously threaten public life health. Therefore, the regulatory factors for heart remodeling caused by hypertension mechanical stress are actively searched, the regulatory mechanism involved in heart failure remodeling is clarified, and the method has a certain clinical significance for delaying and even reversing heart remodeling and improving heart functions. The heart possesses a broad lymphatic network, distributed across the endocardium, epicardium, cardiac myolayers and individual valves of the atrioventricular and atrioventricular conduction systems, with the left and right ventricles being distributed in the greatest number. The heart lymph network absorbs redundant extracellular fluid, solute and metabolic waste, is returned from the heart to the blood circulation system, ensures the homeostasis balance of tissue fluid, can transport immune cells, antigens and the like to lymph nodes, participates in regulating immune response, and is vital to maintaining the normal physiological function of the heart. Hypertension and heart failure can cause cardiac lymphatic dysfunction, cause myocardial edema, aggravate myocardial interstitial fibrosis and the like.
Circular RNAs are a class of non-coding RNA molecules that do not have a 5 'terminal cap and a 3' terminal poly (a) tail, are reverse spliced by exons and/or introns, and form a circular structure by covalent bonds. More and more studies confirm that circular RNAs (circrnas) are involved in vital activities of cells or individuals in different molecular mechanisms than RNA binding proteins (RNA binding protein, RBPs) and translational small peptides, etc., by inhibiting microRNA (miRNA) expression. There is growing evidence that circRNA can be involved in regulating the development and progression of a variety of cardiovascular diseases, but research into the neogenesis of the lymphatic vessels by circrRNA is still in its infancy.
In the prior art, there is a circRNA, namely circRAB3IP, present in human lymphatic endothelial cells (Human lymphatic endothelial cell, hLEC). In the circbase database, the circRNA ID is: hsa_circ_0099132, located at genomic position: chr12:70149163-70150443. As particularly shown in figure 1.
Disclosure of Invention
The invention aims to solve the technical problem of application of CircRAB3IP in preparation of drugs for treating heart failure.
In order to achieve the purpose of the invention, the invention provides application of CircRAB3IP in preparing medicines for preventing or treating heart failure.
The invention provides an application of CircRAB3IP in preparing a medicament for preventing or treating myocardial fibrosis.
The invention provides application of CircRAB3IP in preparing a medicament for preventing or treating myocarditis.
The invention provides application of CircRAB3IP in preparing medicaments for promoting lymphatic vessel neogenesis.
Preferably, the dosage forms of the medicines comprise tablets, powder, granules, capsules, oral liquid, injection or sustained release agents.
The invention provides application of CircRAB3IP in preparation of a heart failure prognosis diagnostic kit.
The invention provides a heart failure prognosis judging system, which comprises a substance for detecting the expression of CircRAB3IP.
The invention provides a heart failure treatment system, which comprises a drug administration system; the drug delivery system contains CircRAB3IP.
Compared with the prior art, the invention has the following beneficial effects:
the invention is proved by in vivo and in vitro experiments: the circRAB3IP can promote lymphatic vessel regeneration, effectively improve heart dysfunction caused by mechanical stress of hypertension, slow down heart reconstruction and myocardial fibrosis, and reduce heart inflammation. The invention provides a new target point and a certain theoretical basis for the treatment of hypertension heart reconstruction.
Drawings
FIG. 1 is a schematic representation of the genomic position of a gene expressing circRAB3 IP;
FIG. 2 is a graph of experimental results confirming the presence of circRAB3IP in lymphatic endothelial cells;
FIG. 3 is a graph comparing the hyperanalysis of over-expressed circRAB3IP with control mice after aortic arch constriction (TAC).
FIG. 4 is a graph showing experimental results of the reduction of persistent mechanical stress induced myocardial hypertrophy in mice over-expressing CircRAB3 IP;
FIG. 5 is a graph of experimental results of overexpression of circRAB3IP to reduce persistent mechanical stress-induced cardiac fibrosis in mice;
FIG. 6 is a graph showing experimental results that overexpression of circRAB3IP can increase cardiac lymphangiogenesis in mice induced by sustained mechanical stress and reduce inflammation.
FIG. 7 is a graph of experimental results of overexpression of circRAB3IP to promote proliferation, migration and lymphangiogenesis of lymphocytes.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments accompanied with the accompanying drawings are described in detail as follows:
the invention provides an application of CircRAB3IP in preparing a medicament for preventing or treating heart failure.
The invention provides an application of CircRAB3IP in preparing a medicament for preventing or treating myocardial fibrosis.
The invention provides application of CircRAB3IP in preparing a medicament for preventing or treating myocarditis.
The invention provides application of CircRAB3IP in preparing medicaments for promoting lymphatic vessel neogenesis.
The dosage forms of the medicine comprise tablets, powder, granules, capsules, oral liquid, injection or sustained release agent.
The invention provides application of CircRAB3IP in preparation of a heart failure prognosis diagnostic kit.
The invention provides a heart failure prognosis judging system, which comprises a substance for detecting the expression of CircRAB3IP.
The invention provides a heart failure treatment system, which comprises a drug administration system; the drug delivery system contains CircRAB3IP.
Examples
In the following examples, mice were supplied by Jiangsu Jiujingyaokang biotechnology Co., ltd, and pK25ssAAV-circRAB3IP AAV9 virus and pAV-CMV-GFP AAV9 control virus were purchased from Shandong Vietnam biotechnology Co. The remaining conventional reagents are commercially available.
Example 1
Determination of circRAB3IP in lymphatic endothelial cells:
extracting hLEC genome DNA (gDNA) and total RNA (RNA reverse transcription into cDNA). The PCR experimental result shows that: using the dispersive primer, the circRAB3IP gene could be amplified from the cDNA of hLEC, but not from gDNA, while its corresponding linear transcript, RAB3IP mRNA, could be amplified by polymerizing the primer, and the amplified product from the dispersive primer in a PCR experiment was subjected to Sanger sequencing, confirming the presence of the correct reverse splice site in the primer amplified PCR product (FIG. 2A). The results of the RNase R digestion experiments showed that linear transcripts of RAB3IP were digested and degraded after RNase R treatment, whereas circRAB3IP was resistant to RNase R treatment (FIG. 2, panel B). This experiment determines that circRAB3IP is actually present in hLEC.
Example 2
Overexpression of circRAB3IP ameliorates sustained mechanical stress-induced cardiac dysfunction in mice:
this experiment compares cardiac function under mechanical stress stimulation in overexpressed circRAB3IP with control mice. FIG. 3 is a graph comparing the hyperanalysis of over-expressed circRAB3IP with control mice after aortic arch constriction (TAC). Control (GFP) and circRAB3IP over-expression (circRAB 3 IP) mice were subjected to TAC or Sham surgery for 6 weeks, cardiac ultrasound examination was performed 6 weeks after surgery, and echocardiography results showed: after 6 weeks of TAC, GFP-TAC mice had significantly reduced left EF% and FS% compared to GFP-Sham group; (EF is left ventricular ejection fraction; FS is left ventricular shortening fraction); compared with the circRAB3IP-TAC mice, the left ventricular ejection fraction and the shortening fraction of the circRAB3IP-Sham mice still decrease, but no statistical difference exists; the EF% and FS% of the circRAB3IP-TAC mice were significantly raised compared to GFP-TAC mice (as shown in panels a-C of fig. 3).
Example 3
The CircRAB3IP over-expressed mice alleviate persistent mechanical stress induced myocardial hypertrophy in mice:
the experiment compares the myocardial cell size and myocardial hypertrophy related gene expression of over-expressed circRAB3IP with that of control mice under mechanical stress stimulation.
FIG. 4 is a graph showing the results of H & E staining (panel A in FIG. 4), gravimetric analysis (panel B in FIG. 4), WGA staining and statistical analysis, and analysis of myocardial hypertrophy related gene qRT-PCR of cardiac tissue from GFP-Sham, GFP-TAC, circRAB3IP-Sham and circRAB3IP-TAC mice: overexpression of circRAB3IP improved cardiac volume increase and ventricular dilation in mice after TAC surgery (fig. 4, panel a); the heart to body weight ratio was significantly reduced (panel B in fig. 4); cardiomyocyte cross-sectional area was significantly reduced (panels C, D in fig. 4); mRNA expression level of gene related to myocardial hypertrophy is obviously reduced (E graph and F graph in FIG. 4).
Example 4
Overexpression of circRAB3IP reduced persistent mechanical stress-induced cardiac fibrosis in mice:
the experiment is a comparison of the degree of myocardial fibrosis after overexpression of circRAB3IP with control mice TAC.
FIG. 5 is a map of the Masson staining and fibrosis area statistics of mouse heart tissue and qRT-PCR analysis of myocardial fibrosis markers. The fibrosis area of the circRAB3IP-TAC group mice was significantly reduced compared to GFP-TAC group mice (panels A, B in FIG. 5). qPCR analysis gave similar results: overexpression of circRAB3IP-TAC reduced the expression level of myocardial fibrosis marker mRNA compared to GFP-Sham group (panels C-E in FIG. 5).
Example 5
Overexpression of circRAB3IP increased cardiac lymphangiogenesis in mice induced by sustained mechanical stress and decreased inflammation:
the experiment is a comparison of the number of post-operative cardiac lymphatic vessels and cardiac inflammation in the over-expressed circRAB3IP and control mice TAC.
FIG. 6 shows mouse heart tissue lymphatic vessels associated immunofluorescence staining, ELISA analysis, qRT-PCR analysis and WesternBlot analysis and inflammation associated molecules qRT-PCR analysis. Lymphatic hyaluronan receptor 1 (lymphatic vessel endothelial hyaluronan receptor-1, LYVE-1) co-stained with CD31 and vascular endothelial growth factor receptor 3 (vascular endothelial growth factor receptor-3, VEGFR 3) fluorescence staining of heart tissue and statistical results showed that: the number of lymphatic vessels positive for circRAB3IP-TAC was significantly increased compared to GFP-TAC mice LYVE-1 and VEGFR3 (FIG. 6, panels A-C). The serum VEGF-C content of the circRAB3IP-TAC mice was significantly increased compared to GFP-TAC (panel D in FIG. 6). qPCR analysis results showed that: the circulating RAB3IP-TAC group lymphatic vessel neogenesis markers mRNA levels were higher than that of the GFP-TAC group (FIG. 6, panels E-G). WB experiments and statistics also show: the expression level of the circulating RAB3IP-TAC group lymphatic vessel neogenesis markers (VEGFR 3 and VEGF-C) protein was higher than that of the GFP-TAC group (FIG. 6, panel H). qPCR analysis of inflammatory factor mRNA levels, the circRAB3IP-TAC group inflammatory factor mRNA levels were lower than that of GFP-TAC group (FIG. 6, panels I-K).
Example 6
Overexpression of circRAB3IP increases lymphocyte endothelial cell proliferation, migration and lymphatic vessel-forming capacity:
this experiment demonstrates the effect of circRAB3IP on lymphocyte proliferation, migration and lymphangiogenesis at the cellular level. Through slow virus infection and puromycin screening, a circRAB3IP over-expression hLEC stable transgenic strain circRAB3IP is constructed, and a circRAB3IP knockdown cell stable transgenic strain sh-circRAB3IP is constructed.
FIG. 7 shows the changes in lymphocyte proliferation, migration, and tube formation capacity after overexpression of circRAB3IP and knock-down of circRAB3IP. CCK8 experiments show that the cell proliferation number of the stable mutant of the circRAB3IP is higher than that of the Vector cells at the time points of 12 hours and 24 hours, and the cell number of the sh-circRAB3IP is slightly lower than that of the control shNC cells at the time points of 12 hours and 24 hours (A in FIG. 7). Lymphatic vessel cannulation experiments showed that the circRAB3IP cells were first cannulated (panel B in fig. 7). Cell scratch experiments at 12 hours, 24 hours and 48 hours and scratch closure area statistics show that: at each time point, the scratch closure area of the circRAB3IP cells was observed to be smaller than that of the Vector cells, and the scratch closure area of the circRAB3IP cells was significantly reduced compared to that of the Vector cells at 48 hours (panels C and D in fig. 7).
The in vivo and in vitro experiments prove that: the circRAB3IP can promote lymphatic vessel regeneration, effectively improve heart dysfunction caused by mechanical stress of hypertension, slow down heart reconstruction and myocardial fibrosis, and reduce heart inflammation.
While the invention has been described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Equivalent embodiments of the present invention will be apparent to those skilled in the art having the benefit of the teachings disclosed herein, when considered in the light of the foregoing disclosure, and without departing from the spirit and scope of the invention; meanwhile, any equivalent changes, modifications and evolution of the above embodiments according to the essential technology of the present invention still fall within the scope of the technical solution of the present invention.
Claims (8)
- Application of CircRAB3IP in preparing medicine for preventing or treating heart failure.
- Application of CircRAB3IP in preparing medicament for preventing or treating myocardial fibrosis.
- Application of CircRAB3IP in preparing medicament for preventing or treating myocarditis.
- Application of CircRAB3IP in preparing medicament for promoting lymphatic vessel neogenesis.
- 5. The use according to any one of claims 1 to 4, wherein the pharmaceutical dosage form comprises a tablet, powder, granule, capsule, oral liquid, injection or sustained release formulation.
- Application of CircRAB3IP in preparing a heart failure prognosis diagnosis kit.
- 7. A heart failure prognosis system, comprising a substance for detecting expression of CircRAB3IP.
- 8. A heart failure treatment system, which is characterized by comprising a drug administration system; the drug delivery system contains CircRAB3IP.
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