CN115792237A - Biomarker for early prediction of heart failure - Google Patents
Biomarker for early prediction of heart failure Download PDFInfo
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- CN115792237A CN115792237A CN202111054134.8A CN202111054134A CN115792237A CN 115792237 A CN115792237 A CN 115792237A CN 202111054134 A CN202111054134 A CN 202111054134A CN 115792237 A CN115792237 A CN 115792237A
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Abstract
The invention discloses a biomarker for early prediction of heart failure. The inventor constructs a protein molecular network dynamically evolving from myocardial infarction to heart failure on an animal model of heart failure after acute myocardial infarction of rats, and screens out Vcan and Col1a1 as early warning markers of heart failure by using regression analysis. Further cell level research shows that after angiotensin II is used for treatment, the expression of Vcan and Col1a1 of cardiac muscle cells is remarkably increased, and after the inhibitor is adopted to respectively intervene the Vcan and the Col1a1, the damage of the angiotensin II to the cardiac muscle cells can be relieved, which indicates that the Vcan and the Col1a1 are closely related to the disease process. Therefore, vcan and Col1a1 can be used as early warning markers of heart failure, can be used for rapid and stable detection, and have important application value.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to a biomarker for early predicting heart failure.
Background
Heart failure is a complex clinical syndrome that is a severe manifestation or late stage of various heart diseases. The prevalence of heart failure is increasing due to aging of the population and increased incidence of myocardial infarction. Partial biochemical markers (such as soluble ST2 and galectin 3) reflect myocardial fibrosis, inflammation and oxidative stress conditions to a certain extent and are helpful for risk stratification and prognosis evaluation of heart failure patients. However, there is still a lack of directly effective biomarkers for early prediction of heart failure in the clinic.
Disclosure of Invention
The object of the present invention is how to predict heart failure early.
The invention firstly protects the application of Vcan and/or Col1A1 in peripheral blood and/or myocardial tissues as biomarkers, which can be A1) or A2):
a1 Preparation of a product for predicting heart failure;
a2 Predicting heart failure;
the use is for the diagnosis and treatment of non-diseases.
The invention also protects the application of the substance for reducing the activity and/or expression quantity of Vcan and/or Col1a1 in peripheral blood and/or myocardial tissue, which can be B1) or B2):
b1 For the preparation of a product for the prevention and/or treatment of heart failure;
b2 Preventing and/or treating heart failure;
the use is for the diagnosis and treatment of non-diseases.
The invention also protects the application of the substance taking Vcan and/or Col1a1 as the target of the medicine in preparing products; the function of the product may be C1) or C2):
c1 Predicting heart failure;
c2 ) prevention and/or treatment of heart failure;
the use is for the diagnosis and treatment of non-diseases.
In the application, the object to be detected by Vcan and/or Col1a1 can be peripheral blood and/or myocardial tissue.
The invention also protects the application of the substance for improving the activity and/or expression quantity of Vcan in peripheral blood and/or myocardial tissue and/or the substance for improving the activity and/or expression quantity of Col1a1 in peripheral blood and/or myocardial tissue in preparing a heart failure mouse model;
the use is for the diagnosis and treatment of non-diseases.
The invention also protects the application of a mouse with increased Vcan activity and/or expression in peripheral blood and/or myocardial tissue and/or increased Col1a1 activity and/or expression in peripheral blood and/or myocardial tissue as a heart failure mouse model;
the use is for the diagnosis and treatment of non-diseases.
The invention also protects the application of the mouse with the increased Vcan activity and/or expression in peripheral blood and/or myocardial tissue and/or the application of the mouse with the increased Col1a1 activity and/or expression in peripheral blood and/or myocardial tissue in preparing and/or screening medicaments; the function of the drug may be C1) or C2):
c1 Predicting heart failure;
c2 ) prevention and/or treatment of heart failure;
the use is for the diagnosis and treatment of non-diseases.
The invention also protects a kit which can comprise a substance for detecting the activity and/or the expression quantity of Vcan and/or a substance for detecting the activity and/or the expression quantity of Col1a 1;
the detection object of the kit is peripheral blood and/or myocardial tissue;
the use of the kit is for predicting heart failure or for preventing and/or treating heart failure.
The kit can specifically comprise a substance for detecting the activity and/or expression quantity of Vcan and/or a substance for detecting the activity and/or expression quantity of Col1a 1.
The invention also provides a heart failure mouse model, and the preparation method comprises the following steps: increasing the activity and/or expression level of Vcan and/or Col1a1 in peripheral blood and/or myocardial tissues of mice.
The inventor of the invention constructs a protein molecular network dynamically evolving from myocardial infarction to heart failure on an animal model of heart failure after rat acute myocardial infarction, and screens out multifunctional proteoglycan (Versican, vcan) and a1 type collagen alpha 1 chain (Col 1a 1) as early warning markers of heart failure by regression analysis. In the animal model, the rat myocardial histology level and the expression of Vcan and Col1a1 in peripheral blood are consistent and increased, and the expression occurs about 10 days after myocardial infarction and is earlier than the expression of BNP reflecting the increase of wall tension. Further cell level research shows that after angiotensin II is used for treatment, the expression of Vcan and Col1a1 of cardiac muscle cells is remarkably increased, and after the inhibitor is adopted to respectively intervene the Vcan and the Col1a1, the damage of the angiotensin II to the cardiac muscle cells can be relieved, which indicates that the Vcan and the Col1a1 are closely related to the disease process. Therefore, vcan and Col1a1 can be used as early warning markers of heart failure, can be used for rapid and stable detection, and have important application value.
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FIG. 1 shows EF% versus FS% change from myocardial infarction to heart failure. A is EF% change at different time after myocardial infarction; b is FS% change at different time after myocardial infarction; c is a representative echocardiogram; * p <0.05vs sham; * P <0.01vs sham.
FIG. 2 shows the expression levels of BNP and NT-proBNP in heart failure from myocardial infarction to heart failure. A is rat serum BNP expression level; b is the expression level of NT-proBNP.
Figure 3 is a heatmap of differentially expressed proteins.
FIG. 4 shows the results of early predictive marker screening.
FIG. 5 shows the expression level changes between Vcan and Col1a 1.
FIG. 6 is a graph showing the effect of BNP and ANP expression levels after 24H treatment of H9c2 cells with different concentrations of Ang II. A is a representative picture of ANP after different concentrations of Ang II, B is a representative picture of ANP expression level change after different concentrations of Ang II, C is a representative picture of BNP expression after different concentrations of Ang II, D is a representative picture of BNP expression level change after different concentrations of Ang II, and p is less than 0.05vs sham; * P <0.01vs sham.
FIG. 7 is a graph of the effect of Vcan and Col1a1 expression levels 24H after treatment of H9c2 cells with different concentrations of Ang II. A is a Vcan immunofluorescence representative picture, B is the expression level of Vcan after Ang II of different concentrations, C is a Col1a1 immunofluorescence representative picture, and D is the expression level of Col1a1 after Ang II of different concentrations.
FIG. 8 shows the change of expression levels of Vcan and Col1a1 after the intervention of the pulse injection. A is the cell level Col1a1 expression level after the pulse generation injection and Ang II treatment, and B is the cell level Vcan expression level after the pulse generation injection and Ang II treatment.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. The examples provided below serve as a guide for further modifications by a person skilled in the art and do not constitute a limitation of the invention in any way.
The experimental procedures in the following examples, unless otherwise indicated, are conventional and are carried out according to the techniques or conditions described in the literature in the field or according to the instructions of the products. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1, vcan and Col1a1 can be used as biomarkers for early prediction of heart failure
1. The early prediction effect of the expression level of multifunctional proteoglycan (Versican, vcan) and type 1 collagen alpha 1 chain (Col 1a 1) in tissues on heart failure is evaluated by adopting a left coronary artery anterior descending ligation model (namely an animal model of heart failure after acute myocardial infarction of rats)
70 SPF-grade healthy male SD rats (hereinafter referred to as rats) with the weight of 270-290g are provided by the experimental animal center of the military medical academy of sciences, and the license number is SCXK (military) 2019-0010. The animals are fed in animal houses of institute of traditional Chinese medicine of Chinese academy of traditional Chinese medicine under the permission of welfare committee of laboratory animals, the room temperature is 24 +/-2 ℃, the humidity is 50 +/-10%, and the animals are alternately cultured in light and dark (12 h of light/12 h of dark) for 24h to supply sterile feed and drinking water.
1. All rats were acclimatized for 3 days prior to the start of the experiment.
2. Molding machine
Model group: rats were weighed, anesthetized with 1% pentobarbital sodium, and were placed in supine position for tracheal intubation with a ventilator. Taking the right lateral decubitus, making a 1cm transverse incision between the 2 nd and 3 rd ribs, performing blunt dissection on fascia and muscle tissue in sequence, cutting a 1cm small opening between the 3 rd ribs after the ribs are exposed, and performing blunt dissection on the muscle tissue to expose the heart. Tearing the pericardium, slightly pushing away the lung lobes with a moist cotton ball, ligating 4mm below the left atrial appendage with a needle depth of 2mm, and rapidly suturing. The intercostal, muscle and skin are sutured by splayed suture respectively, and then the respirator is removed and the animal model of the heart failure after the acute myocardial infarction of the rat is obtained after being placed on an electric blanket.
The sham operation group: essentially the same procedure as for model group, but only threading and not ligation was performed.
3. After 1 week, 2 weeks, 3 weeks or 4 weeks after completion of step 2 (i.e. after modeling), groups of rats were anesthetized with 1 isoflurane and observed for 6 cardiac cycles using a small animal ultrasound imaging system (Vevo 770), measured from M-shaped two-dimensional images of the parasternal short and long axes at the level of papillary muscles, and systolic(s) and diastolic (d) ventricular septum thickness (IVS), left Ventricular Diameter (LVD) and left ventricular posterior wall thickness (LVPW) were measured. The ejection fraction and the shortening fraction are calculated from the M-type two-dimensional image.
The results are shown in FIG. 1 (Sham, model). The results showed that the heart function of the rats gradually decreased with the increase of the molding time, and EF% <55 (p < 0.05) of the fourth model group compared to the sham operation group, indicating that the systolic function was impaired.
4. After the step 3 is finished, collecting blood from abdominal aorta of the model group or the sham operation group by 4-5 mL by using a vacuum blood collection tube (anticoagulation), standing for 1-2 h, centrifuging for 15min at 4 ℃ and 3500r/min, sucking supernatant into an EP tube, and storing at-20 ℃ for later inspection. BNP and NT-proBNP were determined using a fully automated biochemical analyzer.
The results are shown in FIG. 2 (Sham as Sham and Model as Model). The results showed a significant increase in BNP in the fourth week, indicating an increase in ventricular mechanical stress (p < 0.05).
5. After completing the blood collection in step 4, the chest was cut open to expose the heart, the heart was cut off at diastole, and quantitative analysis of cardiac protein mass spectra was performed by Liquid Chromatography (LC) (Bruker Nano-Elute) connected on-line to a hybrid TIMS quadrupole time-of-flight mass spectrometer (Bruker timetof Pro) via CaptiveSpray Nano electrospray ion source.
The differential protein expression is shown in the heatmap of FIG. 3. The results showed that Vcan and Col1a1 were significantly elevated in the second and third weeks, respectively (p < 0.05), and remained at a higher level in the fourth week (p < 0.05).
6. After completion of step 5, the phenotype is correlated with the protein.
The results are shown in FIG. 4.Vcan and Col1a1 have a higher risk level during the evolution of myocardial infarction to heart failure.
The above results indicate that Vcan and Col1a1 can provide more early predictive information than classical markers and can reflect the severity of heart failure.
2. Evaluation of early prediction effect of expression quantity of Vcan and Col1a1 in peripheral blood on heart failure by adopting left coronary artery anterior descending ligation model (namely animal model of heart failure after acute myocardial infarction of rat)
70 SPF-grade healthy male SD rats (hereinafter referred to as rats) with the weight of 270-290g are provided by the experimental animal center of the military medical academy of sciences, and the license number is SCXK (military) 2019-0010. The animals are fed in animal houses of institute of traditional Chinese medicine of Chinese academy of traditional Chinese medicine under the permission of welfare committee of laboratory animals, the room temperature is 24 +/-2 ℃, the humidity is 50 +/-10%, and the animals are alternately cultured in light and dark (12 h of light/12 h of dark) for 24h to supply sterile feed and drinking water.
1. The same as step 1 in the first step.
2. The same as step 2 in the first step.
3. And (3) after the step (2) is finished (namely after modeling) for 1 week, 2 weeks, 3 weeks or 4 weeks, after 1% pentobarbital sodium is used for anesthesia, a vacuum blood collection tube (non-anticoagulation) is used for collecting 4-5 mL of blood for abdominal aorta of a model group or a sham operation group, after standing for 1-2 h, the abdominal aorta is centrifuged for 15min at the temperature of 4 ℃ and 3500r/min, supernatant is sucked into an EP tube, and the expression conditions of Vcan and Col1a1 are detected by an Elisa method.
The results are shown in FIG. 5 (Sham, model): vcan in peripheral blood was significantly elevated with Col1a1 at weeks two and three, respectively (p < 0.05), and remained at a higher level at week four (p < 0.05), consistent with the level of protein expression in the tissues.
The results show that the rat myocardial histology level and the expression of Vcan and Col1a1 in peripheral blood are consistent and increased, and the expression occurs about 10 days after myocardial infarction and is earlier than BNP expression reflecting the increase of wall tension. Therefore, the expression levels of Vcan and Col1a1 in peripheral blood or myocardial tissue can be used for early prediction of heart failure, namely, the Vcan and Col1a1 can be used as biomarkers for early prediction of heart failure.
Example 2 increase in expression of Vcan and Col1a1 in cardiomyocytes following angiotensin II treatment
The expression levels of BNP, ANP, vcan and Col1a1 after the Ang II treatment are detected by adopting an immunofluorescence method, which comprises the following steps:
1. and (4) taking a 96-well plate, inoculating 5000H 9c2 cells in each well, and performing conventional culture for 24H.
2. After the step 1 is completed, randomly grouping, and processing for 24h:
and a con group: add 100. Mu.L basal medium (serum free);
ang ii treatment group: 100 μ L of basal medium (without serum) containing different concentrations of Ang II was added. The treatment concentration of AngII was 1. Mu.M, 10 -1 μM、10 -2 μM、10 -3 μM、10 -4 μM、10 -5 μM、10 -6 μM、10 -7 μ M or 10 -8 μM。
3. After step 2, the culture medium of the con group and the Ang II treatment group is discarded, and the culture medium is lightly washed for 2 times by PBS; then 100. Mu.L of 4% paraformaldehyde was added to each well for fixation for 30min, the paraformaldehyde was discarded, and the wells were gently washed with PBS for 2 times, each for 5min.
4. After completion of step 3, add 100 μ L0.1% Triton-X100 per well and wash 2 times for 5min each; blocking was then performed by adding 100. Mu.L 5% BSA per well for 40min incubation at room temperature, followed by washing 2 times 5min per well with 200. Mu.L PBS; mu.L of primary Antibody (Collagen Type I Monoclonal Antibody (protein, 67288-1-Ig)) or Rabbit Anti-Versican Antibody (bios, bs-2533R) was added to each well, the wells were left at room temperature for 1 hour, left at 4 ℃ overnight, the primary Antibody was recovered the next day and washed gently with PBS for 5 minutes each, 100. Mu.L of fluorescent secondary Antibody was added to each well, the wells were incubated in the dark at room temperature for 2 hours, 200. Mu.L of PBS was added to each well for 3 times each for 5 minutes (dark), 100. Mu.L of phalloidin was added to each well for cytoskeleton staining, 1 hour in the dark at 37 ℃,3 times of PBS washing in 200. Mu.L of each well for 5 minutes (dark), 5 minutes of DAPI staining in 100. Mu.L was added to each well for 5 minutes, 3 times of PBS washing in 200. Mu.L of each well for 5 minutes (dark), and then confocal microscopy was used to obtain BNP, ANP, vcan expression level of 1a of BNP and Colican.
Partial results are shown in FIGS. 6 and 7.
As shown in fig. 6, 10 compared to con group -4 μM、10 -5 μM、10 -6 μM、10 -7 The expression level of BNP and ANP in mu.M AngII-treated H9c2 cells was significantly increased (p)<0.05)。
As shown in fig. 7, 10 compared to con group -3 μM—10 -6 mu.M of the Ang II-treated group Col1a1 showed an increasing trend in expression level at 10 -3 μM-—10 -4 Significantly increased after mu.M Ang II treatment (p)<0.05 ); the expression level of Vcan showed an increasing trend in Ang II treatment group at 10 -3 μM—10 -5 Significantly increased after μ M Ang II treatment (p)<0.05)。
The results show that, at the cellular level, after treatment with angiotensin II, the expression of Vcan and Col1a1 in cardiomyocytes was significantly increased.
Example 3 detection of response of Col1a1 and Vcan to drug intervention prognosis
1. And (4) taking a 96-well plate, inoculating 5000H 9c2 cells in each well, and performing conventional culture for 24H.
2. After the step 1 is completed, randomly grouping, and processing for 24h:
and a con group: add 100 μ L basal medium (without serum);
ang ii treatment group: adding 100 μ L of 10 -4 μ meng ii basal medium (serum free);
pulse activating injection treatment group: 100 μ L of basal medium (without serum) containing different concentrations of pulse-activating injections was added. The treatment concentration of the pulse activating injection is 1/6 (mu L/mL) -1/1 (mu L/mL).
3. After completing step 2, use 10 -4 mu.M of Ang II was treated for 24h.
4. After the step 3 is completed, the culture mediums of the con group, the Ang II treatment group and the pulse-activating injection treatment group are removed by suction, and the culture mediums are lightly washed for 2 times by PBS; then 100. Mu.L of 4% paraformaldehyde was added to each well for fixation for 30min, the paraformaldehyde was discarded, and the wells were gently washed with PBS for 2 times, each for 5min.
5. After completion of step 4, add 100 μ L0.1% Triton-X100 per well and wash 2 times for 5min each; add 100. Mu.L 5% BSA per well and block by incubation at room temperature for 40 min: washing with 200 μ L PBS for 5min for 2 times per well; adding 100 μ L primary Antibody (Collagen Type I Monoclonal Antibody or Rabbit Anti-Versican Antibody) into each well, standing at room temperature for 1 hr, standing at 4 deg.C, and standing overnight; recovering primary antibody the next day, lightly washing with PBS for 5 times, each time for 5min; adding 100 mu L of fluorescent secondary antibody into each hole, and incubating for 2h at room temperature (keeping out of light); add 200. Mu.L PBS to wash 3 times per well, 5min each time (avoid light); adding 100 mu L of phalloidin into each well for cytoskeleton staining, and incubating for 1h at 37 ℃ in a dark place; add 200. Mu.L PBS per well to wash 3 times, 5min each time (keep out of the light); add 100. Mu.L of DAPI stain to each well and incubate for 5min at room temperature; after washing 3 times with 200. Mu.L of PBS per well for 5min (protected from light), the expression level of Vcan and Col1a1 was evaluated by imaging analysis using a confocal microscope.
The results are shown in FIG. 8: after different concentrations of pulse-activating injections and Ang II treatment, the expression levels of Col1a1 and Vcan are reduced compared with the con group (p is less than 0.05). The result shows that Col1a1 and Vcan have good response after the intervention of the pulse-activating injection and can reflect the progress of the heart failure.
The present invention has been described in detail above. It will be apparent to those skilled in the art that the invention can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While the invention has been described with reference to specific examples, it will be appreciated that the invention may be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. The use of some of the essential features is possible within the scope of the claims attached below.
Claims (10)
1. Application of Vcan and/or Col1A1 as biomarker in peripheral blood and/or myocardial tissue, A1) or A2):
a1 Preparing a product for predicting heart failure;
a2 Predicting heart failure;
the use is for the diagnosis and treatment of non-diseases.
2. The application of the substance for reducing the activity and/or expression level of Vcan and/or Col1a1 in peripheral blood and/or myocardial tissue is B1) or B2):
b1 For the preparation of a product for the prevention and/or treatment of heart failure;
b2 Preventing and/or treating heart failure;
the use is for the diagnosis and treatment of non-diseases.
3. The application of a substance taking Vcan and/or Col1a1 as a drug target in preparing products; the function of the product is C1) or C2):
c1 Predicting heart failure;
c2 ) prevention and/or treatment of heart failure;
the use is for the diagnosis and treatment of non-diseases.
4. Use according to claim 3, characterized in that: the object to be detected by Vcan and/or Col1a1 is peripheral blood and/or myocardial tissue.
5. The application of a substance for improving the activity and/or expression of Vcan in peripheral blood and/or myocardial tissue and/or a substance for improving the activity and/or expression of Col1a1 in peripheral blood and/or myocardial tissue in preparing a heart failure mouse model;
the use is for the diagnosis and treatment of non-diseases.
6. The application of a mouse with increased Vcan activity and/or expression in peripheral blood and/or myocardial tissue and/or increased Col1a1 activity and/or expression in peripheral blood and/or myocardial tissue as a heart failure mouse model;
the use is for the diagnosis and treatment of non-diseases.
7. The application of the mouse with the increased Vcan activity and/or expression in peripheral blood and/or myocardial tissue and/or the mouse with the increased Col1a1 activity and/or expression in peripheral blood and/or myocardial tissue in preparing and/or screening medicaments; the function of the drug is C1) or C2):
c1 Predicting heart failure;
c2 Preventing and/or treating heart failure;
the use is for the diagnosis and treatment of non-diseases.
8. A kit, comprising a substance for detecting the activity and/or expression amount of Vcan and/or a substance for detecting the activity and/or expression amount of Col1a 1;
the detection object of the kit is peripheral blood and/or myocardial tissue;
the kit is used for predicting heart failure or preventing and/or treating heart failure.
9. The kit of claim 8, wherein: the kit comprises a substance for detecting the activity and/or expression quantity of Vcan and/or a substance for detecting the activity and/or expression quantity of Col1a 1.
10. A heart failure mouse model is prepared by the following steps: increasing the activity and/or expression level of Vcan and/or Col1a1 in peripheral blood and/or myocardial tissue of mice.
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