CN117180435A - Frizzled2 as target in the treatment of pressure overload myocardial injury - Google Patents
Frizzled2 as target in the treatment of pressure overload myocardial injury Download PDFInfo
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Abstract
The invention discloses an effect of Frizzled2 serving as a target point in treating pressure overload myocardial injury. The aortic arch stenosis (Transverse aortic constriction, TAC) is used for simulating pressure overload myocardial injury in mice, in the pressure overload myocardial injury animal model experiment, the myocardial injury of the mice can be relieved after the adeno-associated virus is knocked down Frizzled2, and the cardiac function of the mice is improved, so that the result of the invention shows that the adeno-associated virus knockdown FZD2 can be used for treating the pressure overload myocardial injury patients, the myocardial injury progress can be delayed, and the life quality of the patients can be improved.
Description
Technical Field
The invention relates to an effect of Frizzled2 serving as a target spot in treating pressure overload myocardial injury, belonging to the technical field of biological medicines.
Background
Pressure overload caused by hypertension, valve disease, etc. is the most common cause of myocardial damage. Currently, beyond treatment for etiology, cardioprotective agents are commonly used to reverse myocardial remodeling caused by pressure overload. However, the current myocardial protection drugs cannot completely relieve myocardial cell injury under pressure overload, and new myocardial protection targets are urgently needed to be discovered.
Frizzled2 (FZD 2 for short) is a protein that plays an important role in the organism and belongs to one of the members of the Frizzled family. The Frizzled family is a family of proteins that are closely related to cell signaling and developmental processes, and they play a key role in physiological processes such as cell polarity, embryonic development, tissue repair, and cancer. FZD2 is expressed on human cell membranes as a seven transmembrane receptor that recognizes and interacts with Wnt proteins. The Wnt signaling pathway is one of the important branches in the cell signaling network, and is critical for embryonic development, tissue repair, and tissue maintenance in adulthood. FZD2, a key component of the Wnt signaling pathway, can regulate processes such as proliferation, differentiation, and migration of cells. Studies have shown that FZD2 plays a role in a variety of physiological and pathological states. In normal embryonic development, FZD2 is involved in regulating embryoid body axis formation and organ development. Furthermore, FZD2 plays an important role in nervous system development, skeletal development, and cardiovascular system development. However, the potential of FZD2 as a therapeutic target for pressure overload myocardial injury has not been explored yet, and the prognosis of pressure overload myocardial injury remains a candid concern.
Disclosure of Invention
The purpose of the invention is that: in order to overcome the defects of the traditional myocardial injury treatment such as heart strengthening, urination promoting and anti-vascular treatment, the invention provides the effect of the Frizzled2 serving as a target point in treating the pressure overload myocardial injury, and animal experiments show that the Frizzled2 can be knocked down to relieve the myocardial injury of mice and improve the heart function of the mice.
In order to achieve the above object, the present invention provides an application of Frizzled2 in preparing a medicament for treating pressure overload myocardial injury.
Preferably, the active ingredient of the medicament is an agent that inhibits the expression or activity of the Frizzled2 gene or protein.
Preferably, the agent is an antibody that specifically inhibits the RNAi, microRNA, shRNA, siRNA, frizzled protein expressed by the Frizzled2 gene or an inhibitor of the activity of the Frizzled2 protein, or a plasmid vector or adeno-associated viral vector comprising the RNAi, microRNA, shRNA or siRNA.
Preferably, the agent is an adeno-associated viral vector capable of specifically inhibiting Frizzled2 gene expression.
Preferably, the adeno-associated viral vector comprises a Frizzled 2-targeted shRNA.
Preferably, the adeno-associated viral vector is an AAV9 virus.
Compared with the prior art, the invention has the following beneficial effects:
adeno-associated virus (AAV) has become one of the most important gene vectors in the field of gene therapy because of its advantages of long-term expression, low toxicity, low immunogenicity, high tissue specificity, etc.; in order to overcome the defects of the traditional myocardial injury treatment such as heart strengthening, urination promoting and vascular resistance treatment, the invention constructs a pressure overload myocardial injury mouse model through aortic arch constriction (Transverse aortic constriction, TAC), and the experimental result in an animal body shows that the adenovirus related virus knockdown FZD2 can be used for treating the pressure overload myocardial injury patient, can delay the myocardial injury progress and improve the life quality of the patient.
Drawings
FIG. 1. Detection of knockdown results of FZD2 by Western immunoblotting;
FIG. 2. Comparison of ejection fraction between four groups; ns: no statistical difference; * : p is less than 0.05; * *: p is less than 0.01; * **: p < 0.001);
FIG. 3. Comparison of the weight/tibia ratio between four groups; ns: no statistical difference; * : p is less than 0.05; * *: p is less than 0.01; * **: p < 0.001.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below.
The test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
Examples
Pressure overload myocardial injury was simulated in mice using aortic arch stenosis (Transverse aortic constriction, TAC). Adult male C57BL/6J mice (8 weeks old, 20-25G) were used, the mice were anesthetized, then were tracheal cannulated, hair was cut off from the anterior chest area of the mice under assisted breathing by an anesthesia respirator, sterilized, skin was cut off between two three ribs on the left edge of the sternum, hemostats separated subcutaneous muscles, second ribs were cut off, chest expander spread the chest wall, aortic arch was separated with micropeels, 27G needle was placed across the aortic arch, silk was ligated, needle was gently withdrawn, and TAC was successfully induced. SHAM group only threading is not ligatured, and the rest processes are the same as TAC group. The animals were randomized into control adeno-associated virus (AAV-Con) and FZD2 knock-down adeno-associated virus (AAV-shFZD 2) treatment groups, and the mice were then monitored for cardiac function by tail vein injection on the same day of surgery.
1. Adeno-associated virus preparation and injection:
adeno-associated virus is entrusted and metabiological preparation, shRNA fragments (5'-GAAAGAAGGCTGCACTATACT-3', SEQ ID NO: 1) of targeted mice FZD2 are constructed into pcAAV-cTNT-MCS-WPRE vectors, shRNA is started by U6, and polyA tail is stopped to express; after the carrier is constructed, the carrier and the packaging system plasmid are transfected into HEK-293T cells together for virus packaging. rAAV9 targeting adeno-associated virus to shRNA of mouse FZD2 by tail vein injection at 1X 10 11 vg (vector genome) was administered to mice that were TAC-operated or SHAM-group completed. The negative control (rAAV 9 eGFP) alone expressed enhanced green fluorescent protein (eGFP). Two weeks later, FZD2 knockdown efficiency was assessed by western blot, as shown in figure 1.
2. Experimental animals and animal model preparation:
SPF-class male C57BL/6J mice (purchased from Shanghai Jieshijie laboratory animal Co., ltd.) are selected, the week age is 8 weeks, the weight is 20-25g, and tracheal intubation articles, fixing adhesive tapes and the like are prepared; the mice are placed in the anesthesia closed box, and are quickly fixed on the operation plate in a supine mode after muscle strength disappears; aiming the cold light source at the neck of the mouse, slightly pulling out the tongue of the mouse by using forceps, and under the irradiation of the cold light source, seeing a tracheal opening with stronger refraction performance consistent with the breathing frequency, rapidly inserting a tracheal cannula into the airway, and rapidly sucking isoflurane again if the mouse has a waking sign in the period; connecting to an anesthesia respirator, and if the intubation is successful, observing the fluctuation of the thoracic cavity of the mouse along with the breathing machine frequency; shearing off the hair in the chest area of the mouse by scissors, and sterilizing by iodophor; the skin is cut off between two third ribs on the left edge of the sternum, subcutaneous muscles are separated by utilizing hemostats, after ribs are exposed, the second ribs are cut off along the left edge of the sternum, and a chest expander is placed in the chest expander in a homeopathic manner and the chest wall is expanded; the blood can be sucked by a sterilized cotton swab or a small cotton ball, and the surgical field is exposed; carefully separating thymus along the middle of bilateral thymus with micropunches to expose ascending aorta and branches; continuing to separate the aortic arch and redundant tissues outside the bifurcation by using the micro forceps, and fully exposing the aortic arch and the first branch and the second branch; a No. 5 silk thread passes through the brachiocephalic trunk and the left common carotid artery by means of a homemade tool, a 27G needle head is transversely arranged on the aortic arch, and ligature silk thread is arranged on the 27G needle head; gently withdraw the needle; after the non-active hemorrhage is determined, the chest wall and the muscle are sutured layer by layer, the chest wall is squeezed lightly at the end of closing the chest to remove the gas in the chest as much as possible, and finally the skin is sutured; the iodophor disinfects skin, is connected to a small anesthesia-free breathing machine, and is put back into a mouse cage after the mouse is completely awake, and the temperature around the mouse can be increased by using a heater to accelerate the mouse to wake up; SHAM group only threading is not ligatured, and the rest processes are the same as operation group.
3. Experimental grouping
Experiments were performed in 4 groups: sham+aav-Con group; sham+aav-shFZD2 group; tac+aav-Con group; tac+aav-shFZD2 group. Viral titers were all 1X 10 11 VG/mouse.
4. Evaluation of mouse cardiac Functions by echocardiography
Echocardiography was examined at 8 weeks with a probe frequency of 30MHz. In particular, after isoflurane-tingling animals, M-mode images were recorded while the heart rate of the mice was maintained between 450 and 550 beats/min. The method is characterized in that a long-axis section beside the sternum and a four-cavity section B-Mode image of the apex of the heart are collected. The parasternal left ventricular short axis was taken, 2D ultrasound was taken to show the left ventricular short axis section, the left ventricular motion was recorded using M-ultrasound at the papillary muscle level, and its Left Ventricular Ejection Fraction (LVEF) was mainly observed. The mice of each group were compared for heart morphology and functional changes. All measurements are averages of 5 consecutive cardiac cycles. The results show that: the heart function index of mice in the TAC+AAV-Con group is obviously lower than that of mice in the SHAM+AAV-Con group, the heart function of the mice in the TAC group+AAV-shFZD 2 group is improved, and the LVEF of the mice in the TAC+AAV-shFZD2 group is 18.98 percent higher than that of the mice in the TAC+AAV-Con group (P < 0.05) (see figure 1); the heart to tibia ratio was lower for mice in the tac+aav-shFZD2 group than for mice in the tac+aav-Con group (P < 0.05) (see figure 2).
In conclusion, after Frizzled2 is knocked down, myocardial injury of a mouse can be relieved, and cardiac function of the mouse is improved, so that the result of the invention shows that the adenovirus related virus knocked down FZD2 can be used for treating patients with pressure overload myocardial injury, myocardial injury progress can be delayed, and life quality of the patients can be improved.
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.
Claims (5)
- Use of frizzled2 in the manufacture of a medicament for the treatment of pressure overload myocardial injury.
- 2. The use according to claim 1, wherein the active ingredient of the medicament is an agent which inhibits the expression or activity of the Frizzled2 gene or protein.
- 3. The use according to claim 2, wherein the agent is an antibody to the RNAi, microRNA, shRNA, siRNA, frizzled protein or an inhibitor of the activity of the Frizzled2 protein which specifically inhibits the expression of the Frizzled2 gene, or is a plasmid vector or an adeno-associated viral vector comprising said RNAi, microRNA, shRNA or siRNA.
- 4. The use of claim 3, wherein the agent is an adeno-associated viral vector capable of specifically inhibiting Frizzled2 gene expression.
- 5. The use of claim 4, wherein the adeno-associated viral vector comprises a Frizzled 2-targeted shRNA.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311148483.5A CN117180435A (en) | 2023-09-06 | 2023-09-06 | Frizzled2 as target in the treatment of pressure overload myocardial injury |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311148483.5A CN117180435A (en) | 2023-09-06 | 2023-09-06 | Frizzled2 as target in the treatment of pressure overload myocardial injury |
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- 2023-09-06 CN CN202311148483.5A patent/CN117180435A/en active Pending
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