CN109364248B - Use of ENaC and inhibitors thereof for preventing, alleviating and/or treating atherosclerosis - Google Patents
Use of ENaC and inhibitors thereof for preventing, alleviating and/or treating atherosclerosis Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention discloses application of ENaC and an inhibitor thereof in preventing, relieving and/or treating atherosclerosis, and belongs to the technical field of medicines. The present invention uses LDL‑/‑Mouse and gamma-ENaC‑/‑LDLR‑/‑The results of an atherosclerosis model obtained by high fat diet induction of an experimental object show that the model is similar to LDLR‑/‑In comparison with mice, the aortic plaque area of the mice with the ENaC gene deletion or inhibition is obviously reduced. This indicates that ENaC has the effect of promoting aortic plaque formation and promoting atherosclerosis. Aiming at the functions of the ENaC, the invention provides the application of the ENaC as a drug target in screening drugs for preventing, relieving and/or treating atherosclerosis and the application of an inhibitor of the ENaC in preparing drugs for preventing, relieving and/or treating atherosclerosis. The invention provides a new target and a medicine for preventing, relieving and/or treating atherosclerosis, and has important significance for clarifying a molecular mechanism in the development process of atherosclerosis and searching a molecular target for treating atherosclerosis.
Description
Technical Field
The invention relates to a new target for treating atherosclerosis and a medicament thereof, in particular to application of ENaC and an inhibitor thereof in preparing a medicament for preventing, relieving and/or treating atherosclerosis. The invention belongs to the technical field of medicines.
Background
In recent years, the incidence of serious cardiovascular diseases in China, including hypertension, coronary heart disease, peripheral vascular diseases and the like, is remarkably increased. Epidemiological investigation shows that the number of patients with cardiovascular diseases in China is as high as 2.3 hundred million. In 2010, 5.8 million people in China have at least one risk factor related to cardiovascular diseases, and if corresponding basic research and clinical intervention cannot be improved, the risk of cardiovascular diseases is increased by 50% by 2030. At present, cardiovascular and cerebrovascular diseases are the first leading cause of death of the population in China, and in the death factors of the population in cities and rural areas, the cardiovascular diseases account for 41.0 percent and 40.3 percent respectively, and the cardiovascular diseases become one of the most important public health problems in China. The basis of cardiovascular and cerebrovascular disease is Atherosclerosis (AS), which can thicken, stiffen, and narrow the walls of the arteries, leading to many cardiovascular events. Rupture of atherosclerotic unstable plaque, platelet aggregation, and acute stenosis and occlusion of coronary arteries by thrombosis are important causes of Acute Coronary Syndrome (ACS).
The macroscopic lesions in the earliest stages of atherosclerosis are lipid streaks, which are composed primarily of macrophage-derived foam cells that take up large amounts of cholesterol. Monocytes in the blood circulation adhere to the activated endothelial cells at vulnerable sites of the artery, initiating the formation of lipid streaks, and the adhered monocytes subsequently migrate under the intima by attraction of locally produced chemoattractant molecules and further differentiate into macrophages. A large amount of cholesterol accumulates in macrophages to form foam cells, a characteristic pathophysiological process in the early stages of atherogenesis. Atherosclerosis occurs as a result of the combined action of multiple factors, and a plurality of atherosclerosis risk factors are found at present, but the treatment and control effects are not ideal, and the lipid-lowering and anti-inflammatory treatment is the most important treatment measures at present.
The expression of the epithelial cell sodium channel, ENaC, in the vascular endothelium plays an important role in maintaining the homeostasis of sodium ions in the body and controlling systemic blood pressure, and abnormal activation of ENaC can increase sodium reabsorption, leading to hypertension. ENaC is mainly distributed in epithelial cells of the distal nephron, colon, lung, salivary glands. The ENaC belongs to an ENaC/DEG supergene family, mainly comprises three subunits alpha, beta and gamma (different types of subunits in different systems), is a glycosylated macromolecular protein on a cell membrane, and mainly regulates and controls the transport of sodium ions across epithelial cells. Because of its sensitivity to the diuretic Amiloride (amioride), it is also known as the Amiloride sensitive epithelial sodium channel (Sun Y, Zhang JN, Zhao D, et al. role of the epithelial sodium channel in salt-sensitive hypertension [ J ]. Acta Pharmacol Sin,2011,32(6): 789-. Recent studies have shown that ENaC is also expressed in vascular endothelium and vascular smooth muscle, for example, in Human Umbilical Vein Endothelial Cells (HUVEC), mouse aorta and human artery endothelial cells, and other endothelial cell lines (e.g., EA. hy926, GM7373 and HMEC), and that ENaC expression can be detected (Kusche-Vihrog K, Jeggle P, Oberleithner H. the role of ENaCin vascular endothelial [ J ]. Pflugers Arch,2014,466(5): 851-859.). In addition, ENaC is also expressed in human ocular vascular smooth muscle cells and cerebral microvasculature (Kusche-Vihrog K, Tarjus A, Fels J, et al. the epithelial Na + channel: a new layer in the vascular [ J ]. Curr Opin Newrol Hypertens,2014,23(2): 143. fig.148.).
The inventor finds that the inhibition of vascular ENaC can increase the endothelial nitric oxide level caused by salt decrease in earlier research. Based on the above research, it is believed that ENaC may play an important role in the pathophysiological processes characteristic of atherogenesis. Therefore, the inventor uses LDLR-/-Receptor knockout mice and ENaC/LDLR-/-The double-gene knockout mouse is an experimental object, an atherosclerosis mouse model is obtained through high-fat diet induction, and the study on the aortic tree plaque area shows that the area of the aortic tree plaque can be obviously reduced through the ENaC gene knockout or the use of an ENaC inhibitor. Therefore, the ENaC has the function of promoting the generation and the development of atherosclerosis. The invention provides a new target and a medicine for preventing, relieving and/or treating atherosclerosis, and has important significance for clarifying a molecular mechanism in the development process of atherosclerosis and searching a molecular target for treating atherosclerosis.
Disclosure of Invention
The invention aims to determine the correlation between the activity of ENaC and atherosclerosis and provide a novel target point and a medicament for preventing, relieving and/or treating atherosclerosis.
The purpose of the invention is realized by the following technical scheme:
the invention uses LDLR-/-Receptor knockout mice and ENaC/LDLR-/-The double-gene knockout mouse is an experimental object, an atherosclerosis mouse model is obtained through high-fat diet induction, and the study on the aortic tree plaque area shows that the area of the aortic tree plaque can be obviously reduced through the ENaC gene knockout or the use of an ENaC inhibitor. From the above results, it is known that when atherosclerosis occurs, the defect of the ENaC gene reduces the plaque area, and relieves atherosclerosis. Therefore, the ENAC has the function of promoting the development of atherosclerosis and can be used as a drug target.
On the basis of the research, the invention provides application of ENaC as a drug target in screening drugs for preventing, relieving and/or treating atherosclerosis.
Constructing an in vitro cell model or an animal model of ENaC gene overexpression, and screening drugs for preventing, relieving and/or treating atherosclerosis; the ENaC gene can also be used as a target gene in gene therapy, and the medicine and/or biological reagent for preventing, relieving and/or treating atherosclerosis is designed and prepared, and the purpose of preventing, relieving and/or treating atherosclerosis is achieved through a gene engineering technology. For example, using ENaC as target gene, designing double-stranded siRNA capable of interfering ENaC expression, after chemically synthesizing, injecting into human body to silence ENaC gene by RNA interference method to treat atherosclerosis; the mutant of the ENaC can be designed and constructed, enters cells after being injected, and competes for an action substrate of the ENaC prototype, so that the function of the ENaC is inhibited, and the treatment purpose is achieved; in addition, a small molecule compound inhibitor can be designed by taking the ENaC as a target spot, and a molecule capable of specifically inhibiting the ENaC is discovered by screening an in vitro cell model or an animal model with the ENaC gene overexpressed, so that a novel therapeutic molecule is provided for treating atherosclerosis.
Furthermore, the invention also provides application of the inhibitor of ENaC in preparing a medicament for preventing, relieving and/or treating atherosclerosis.
Wherein, the inhibitor of ENaC is preferably one of amiloride, siRNA of ENaC gene, RNA interference vector of ENaC gene, antibody of ENaC and other inhibitors capable of inhibiting the expression of ENaC.
Furthermore, the invention also provides a medicament with the effects of relieving, preventing and/or treating atherosclerosis, which comprises the inhibitor of ENaC.
Wherein, the inhibitor of ENaC is preferably one of amiloride, siRNA of ENaC gene, RNA interference vector of ENaC gene, antibody of ENaC and other inhibitors capable of inhibiting the expression of ENaC.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention discovers a new function of ENaC, namely ENaC has the function of exacerbating atherosclerosis, and provides a target for developing a medicament for preventing, relieving and/or treating atherosclerosis based on the function of ENaC in exacerbating atherosclerotic diseases.
(2) Inhibitors of ENaC are provided as useful for the preparation of new medicaments for the prevention, alleviation and/or treatment of atherosclerosis.
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FIG. 1 is a LDLR-/-Mouse, gamma-ENaC/LDLR-/-Double gene knockout mouse and Amylori gavage LDLR-/-Aortic tree oil red O staining pattern of mice.
FIG. 2 is a LDLR-/-Mouse, gamma-ENaC/LDLR-/-Double gene knockout mouse and Amylori gavage LDLR-/-Statistical plot of aortic tree oil red O staining pattern plaque area for mice.
The results indicate that ENaC gene knockout or the use of amiloride can significantly reduce the plaque area of the aortic tree (NS, no significant difference).
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Experimental animals and breeding:
species, sex, week age and source of experimental animals: c57BL/6(WT) mice and LDLR gene knockout (LDLR)-/-) Mouse and gamma-ENaC-/-LDLR-/-Double knockout mice, male, 8 weeks old. C57BL/6 mice were purchased from Biotech, Inc., Viton, Beijing; LDLR knockout mice and γ -ENaC knockout mice were purchased from seye corporation; gamma-ENaC-/-LDLR-/-Double knockout mice LDLR knockout mice and gamma-ENaC-/-And (3) hybridizing a knockout mouse.
Experimental animal feed formula
High fat diet (HFD, available from Beijing Huafukang Biotech Co., Ltd., in terms of AIN-76A Western diets, caloric percentage: protein 15.8%, fat 40%, carbohydrate 44.2%); low fat feed (NC, from Beijing Huafukang Biotech limited, cat # D12450B, percent caloric: 20% protein, 10% fat, 70% carbohydrate)
Animal feeding conditions: all experimental mice were housed in the SPF-rated animal room of Hayada, university Hospital. The mouse is illuminated alternately every 12 hours at the temperature of 24 +/-2 ℃ and the humidity of 40-70 percent, and the mouse can eat freely by drinking water.
Example 1 mouse Atherosclerosis model (AS) acquisition
1. Grouping experimental animals: selecting male LDLR-/-mice and gamma-ENaC with the age of 8 weeks and the weight of 19-25g-/-LDLR-/-Double knockout mice fed with High Fat Diet (HFD) and low fat diet (NC) separately and divided into LDLR-/-HFD group, LDLR-/-NC group, gamma-ENaC-/-LDLR-/-HFD group, gamma-ENaC-/-LDLR-/-NC group, LDLR-/-HFD intragastric Amiloride (Amiloride) group, LDLR-/-The NC intragastric amiloride groups consisted of 6 groups of 20 individuals each.
2. Operating process of atherosclerosis model through high fat induction
By LDLR Gene knockout (LDLR)-/-) Mouse and gamma-ENaC-/-LDLR-/-Double-gene knockout of mice, establishment of AS models, phenotype correlation analysis, and definition of the function of ENaC gene on atherosclerosis. Mice were sacrificed and samples were collected from 8 weeks of age with HFD group on full high fat diet for 16 weeks and NC group on full low fat diet for 16 weeks.
Example 2 plaque area determination in AS model mice
1. Mouse terminal tissue sampling
1) The 6 groups of mice in example 1 were sacrificed and the aorta was carefully removed from the aortic root up to the common iliac bifurcation;
2) separating all outer membranes and fat under a body microscope;
3) fixing the separated blood vessel in 4% neutral formaldehyde, and standing overnight in a 4oC refrigerator;
4) taking out aorta with ddH2Washing for 3 times (5 min each) to remove the attached formaldehyde solution;
5) longitudinally dissecting blood vessels under a body microscope;
6) oil-formulated red use solution (stock solution: ddH2O is 3:2), standing for 10min, and then using;
7) putting the aorta into an oil red dyeing solution, and dip-dyeing for 2h at room temperature;
8) discarding the dye solution, and washing the dye solution with 70% alcohol; until the vessel wall appears white and the plaque remains bright red
9) Blood vessels were carefully flattened, images were collected with a high resolution camera, and quantified using Image-J Image analysis software (oil red O stock solution 0.5 g oil red O +100 ml 100% isopropanol, oil red O stain (working solution): v (oil red O stock solution)/V (H)2O)=3/2)
Aortic tree plaque area (%) -. Total plaque area/Total aortic tree area 100%
The above results show LDLR-/-Mouse, gamma-ENaC-/-LDLR-/-Double gene knockout mice and LDLR-/-Atheromatous lesions developed in the gavage amiloride mice under induction of HFD. And LDLR-/-MouseBy comparison, gamma-ENaC-/-LDLR-/-Double gene knockout mice and LDLR-/-Aortic plaque area was significantly reduced in gavage amiloride mice.
These results indicate that the ENaC gene can significantly contribute to atherosclerosis. The knockout of the ENaC gene or the use of an inhibitor thereof can reduce atherosclerotic lesions, and thus can be used for preparing a medicament for preventing, alleviating and/or treating atherosclerotic diseases.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (2)
1. The application of gamma-ENaC as a drug target in screening drugs for preventing, relieving and/or treating atherosclerosis.
2. The application of the inhibitor of the gamma-ENaC in preparing the medicines for preventing, relieving and/or treating atherosclerosis is disclosed, wherein the inhibitor of the gamma-ENaC is one of siRNA of the gamma-ENaC gene, RNA interference vector of the gamma-ENaC gene or antibody of the gamma-ENaC.
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