CN117815360A - Application of Spexin active polypeptide in preparation of medicines for enhancing myocardial contractility - Google Patents
Application of Spexin active polypeptide in preparation of medicines for enhancing myocardial contractility Download PDFInfo
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- CN117815360A CN117815360A CN202410024869.3A CN202410024869A CN117815360A CN 117815360 A CN117815360 A CN 117815360A CN 202410024869 A CN202410024869 A CN 202410024869A CN 117815360 A CN117815360 A CN 117815360A
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to application of Spexin active polypeptide in preparation of a medicament for enhancing myocardial contractility, and belongs to the technical field of medicaments for enhancing myocardial contractility. The invention provides a novel pharmaceutical application of a Spexin active polypeptide, namely an application of the Spexin active polypeptide in preparing a medicament for enhancing myocardial contractility, wherein the amino acid sequence of the Spexin active polypeptide is NWTPQAMLYLKGAQ. Animal experiments prove that the Spexin active polypeptide can increase calcium transient in cardiac muscle cells, strengthen the contractility of the cardiac muscle cells, improve the imbalance of calcium homeostasis of the cardiac muscle cells during chronic heart failure, further protect heart functions, reduce death rate and improve long-term prognosis. The Spexin active polypeptide is applied to the preparation of medicaments for enhancing myocardial contractility, and the novel clinical application of the Spexin active polypeptide is developed, so that the Spexin active polypeptide is hopeful to be developed into a novel medicament for safely and effectively preventing and treating heart diseases.
Description
Technical Field
The invention belongs to the technical field of medicaments for enhancing myocardial contractility, and particularly relates to application of Spexin active polypeptide in preparation of medicaments for enhancing myocardial contractility.
Background
Heart failure is the ultimate outcome and leading cause of death for most cardiovascular diseases, and has high disability and mortality, which has become one of the global major public health problems. With the increasing aging of population, the prevalence rate and hospitalization rate of heart failure are continuously rising, and the search for effective treatment means of heart failure is still an important point and a difficult problem of world public health.
Myocardial contractility refers to an inherent property of myocardial fibers that changes its contraction strength and velocity independent of preload and afterload. At a constant heart rate, the greater the myocardial contractility, i.e., the greater the intensity of contraction, the faster the contraction rate, the greater the stroke volume, and vice versa. The heart failure causes a decrease in myocardial contractility, and imbalance in myocardial cell calcium homeostasis is an important mechanism. Traditional inotropic drugs increase myocardial contractility by increasing the concentration of calcium ions in myocardial cells, but often cause malignant arrhythmia and even increase mortality, so searching for drugs capable of effectively improving heart contractility and clinical symptoms of heart failure patients and reducing hospitalization rate and occurrence rate of adverse events gradually becomes a hot spot of clinical research.
Spexin active polypeptide is a novel endogenous bioactive peptide hormone, and researches prove that the Spexin active polypeptide plays a key role in physiological function regulation of organism pain sense, appetite, defecation, glycolipid metabolism, water-salt balance, anti-inflammatory and the like. However, whether Spexin active polypeptide is involved in myocardial contractility regulation has not been reported.
Disclosure of Invention
The invention provides a novel pharmaceutical application of Spexin active polypeptide, namely, an application of Spexin active polypeptide in preparing a medicament for enhancing myocardial contractility.
The technical scheme of the invention is as follows:
use of a Spexin active polypeptide in the manufacture of a medicament for enhancing myocardial contractility.
Further, the amino acid sequence of the Spexin active polypeptide is NWTPQAMLYLKGAQ.
Further, the medicament for enhancing myocardial contractility takes the Spexin active polypeptide as the only active ingredient or one of the active ingredients.
Further, the content of Spexin active polypeptide in the medicament for enhancing myocardial contractility is 0.1-99 wt%.
Further, the medicament for enhancing the myocardial contractility further comprises pharmaceutically acceptable auxiliary materials and/or carriers.
Further, the drug for enhancing myocardial contractility is used for enhancing myocardial contractility of mammals.
Further, the mammal is a human or a mouse.
Furthermore, the medicament for enhancing the myocardial contractility is a parenteral administration dosage form, in particular an injection administration dosage form.
Further, the drugs for enhancing myocardial contractility include drugs for treating heart failure caused by heart failure-related disorders and drugs for heart failure-related complications.
Further, the heart failure-associated condition includes coronary heart disease, hypertension, valvular disease, myocarditis, cardiomyopathy, arrhythmia, metabolic disease, tumor, and/or a tumor treatment-related cardiac disease, or a combination thereof.
Further, the metabolic disease includes: diabetes, dyslipidemia, thyroid disorders, hyperuricemia, metabolic syndrome, or a combination thereof.
The invention has the beneficial effects that:
the invention provides a new application of a Spexin active polypeptide to the enhancement of myocardial contractility, and in vitro experiment results prove that the Spexin incubation can increase calcium transient in myocardial cells and enhance myocardial cell contractility; the animal experiment result of heart failure proves that the Spexin active polypeptide can improve the imbalance of the calcium steady state of cardiac myocytes in heart failure, increase the contractility of the cardiac myocytes, and improve the cardiac function and long-term survival rate of mice.
The Spexin active polypeptide is applied to the preparation of medicaments for enhancing myocardial contractility, and the novel clinical application of the Spexin active polypeptide is developed. The Spexin active polypeptide has obvious function of enhancing myocardial contractility, improves heart function of heart failure mice and reduces death rate, and is expected to become a novel effective treatment means for preventing and treating heart failure.
Drawings
FIG. 1 is a graph showing the comparison of the rate of reduction of myocardial cell sarcomere in mice before and after incubation with different concentrations of Spexin active polypeptide of example 1;
FIG. 2 is a representation of the contraction of mouse cardiomyocytes before and after incubation with a Spexin active polypeptide of example 1;
FIG. 3 is a graph showing comparison of the magnitude of calcium transients in mouse cardiomyocytes before and after incubation with Spexin-active polypeptide of example 1;
FIG. 4 is a graph showing comparison of the calcium transient time profiles of mouse cardiomyocytes before and after incubation with a Spexin active polypeptide of example 1;
FIG. 5 is a graph showing the comparison of the amplitude of calcium transients in the cardiomyocytes of mice in example 2 for each group;
FIG. 6 is a graph showing the comparison of the calcium transient time profiles of cardiomyocytes in mice of each group of example 2;
FIG. 7 is a graph showing comparison of time constants of calcium decrease in myocardial cells of mice in each group in example 2;
FIG. 8 is a representative photograph of each group of mouse cardiomyocytes stained for Fluo-3 in example 2;
FIG. 9 is a graph showing the comparison of resting calcium levels of cardiomyocytes in mice of each group in example 2;
FIG. 10 is a representative graph of the cardiac ultrasound measurements of the mice of example 2;
FIG. 11 is a graph showing the comparison of LVEF test results for each group of mice in example 2;
FIG. 12 is a graph showing comparison of LVFS test results of mice in example 2;
FIG. 13 is a comparison of survival curves of mice in each group of example 2.
Detailed Description
The following embodiments are used for further illustrating the technical scheme of the present invention, but not limited thereto, and all modifications and equivalents of the technical scheme of the present invention are included in the scope of the present invention without departing from the spirit and scope of the technical scheme of the present invention. The process equipment or apparatus not specifically noted in the following examples are all conventional equipment or apparatus in the art, and the raw materials and the like used in the examples of the present invention are commercially available unless otherwise specified; unless specifically indicated, the technical means used in the embodiments of the present invention are conventional means well known to those skilled in the art.
Example 1
This example examined the effect of Spexin-active polypeptides on mouse cardiomyocyte contractions.
The specific method for incubating cardiomyocytes with the Spexin active polypeptide comprises the following steps:
1. adult mouse cardiomyocyte isolation: adult C57BL/6 mice were anesthetized after intraperitoneal injection of heparin 0.1m (l 50 mg/ml), hearts were rapidly isolated, placed in a pre-chilled calcium-containing desktop fluid at 4 ℃, aortic roots were suspended and connected to Langendorff perfusion apparatus, perfused at 37℃with a calcium-free perfusate, and a calcium-free desktop fluid containing BSA (0.75 mg/ml) and type II collagenase (1 mg/ml) was added. Removing heart, cutting off ventricular part, and collecting CaCl 2 (200. Mu.M) and BSA (1%) were gently sheared and gently blown in a calcium bench-top solution, and the filtrate was filtered through a filter screen, the cardiomyocyte suspension.
2. Myocardial cell contractility assay: a small amount of cell suspension is sucked and placed in a cell perfusion groove, and perfusion is carried out by using an oxygen-containing calcium desk type liquid, and electric field stimulation with constant frequency and constant voltage of 1Hz is given to myocardial cells. Changes in myocardial cell sarcomere length, i.e., changes in length upon individual cardiomyocytes dilating and contracting, are recorded and measured.
3. Cardiomyocyte calcium transient assay: cardiomyocytes were incubated with Fluo-3 and rinsed 3 times with calcium desk top solution. A small amount of the cell suspension was withdrawn and placed in a cell perfusion cell, and electric field stimulation was given at a constant frequency of 1 Hz. The fluorescence intensity of the cells reflects the change condition of the calcium in the myocardial cells, and the amplitude of the calcium transient of the myocardial cells is calculated.
4. Myocardial cell resting calcium assay: the cardiomyocytes stained with Fluo-3 were washed with a calcium-free bench top solution and assayed for resting calcium using a confocal microscope. Image J counted the fluorescence value of individual cardiomyocytes, which represents the intracellular calcium content.
Spexin incubation concentration: and incubating the cardiomyocytes in the cell perfusion tank with 10, 100 and 1000nM Spexin active polypeptide, and detecting the contractility and calcium transient amplitude of the cardiomyocytes before and after incubation with the Spexin active polypeptide, respectively, wherein the number of the detected cardiomyocytes is not less than 15.
FIG. 1 is a graph comparing the rate of reduction of myocardial cell sarcomere in mice before and after incubation with different concentrations of Spexin active polypeptide; FIG. 2 is a representation of mouse cardiomyocyte contraction before and after incubation of a Spexin active polypeptide; as shown in FIGS. 1 and 2, the sarcomere shortening of cardiomyocytes incubated with Spexin-active polypeptide was significantly increased over that before incubation, while further studies have found that Spexin-active polypeptides 10, 100 and 1000nM were able to increase the sarcomere shortening of cardiomyocytes and were dose-dependent. This suggests that the Spexin active polypeptide is capable of enhancing cardiomyocyte contractility.
FIG. 3 is a graph showing comparison of the magnitude of calcium transients in mice cardiomyocytes before and after incubation with Spexin-active polypeptide; FIG. 4 is a graph showing comparison of the calcium transient time profiles of mouse cardiomyocytes before and after incubation of Spexin active polypeptide; as shown in FIGS. 3 and 4, cardiomyocytes were incubated in a perfusion cell with 1000nM of Spexin-active polypeptide, and changes in the fluorescence intensity in the cells before and after incubation of Spexin-active polypeptide were observed, indicating changes in intracellular calcium content. The results showed that after incubation of cardiomyocytes with Spexin-active polypeptide, intracellular Ca 2+ The maximum value of the change was significantly increased over that before incubation. It can be seen that incubation of the Spexin active polypeptide increased the mouse cardiomyocyte calcium transient, suggesting that the Spexin active polypeptide can enhance cardiomyocyte contractility by increasing the calcium transient in the cardiomyocytes.
Example 2
This example examined the effect of Spexin-active polypeptide on cardiac myocyte calcium homeostasis in heart failure mice.
The experimental animals used in the invention are 8-10 week male adult C57BL/6 mice, and the weight is 22-25g, and the experimental animals are purchased from Vetolihua experimental animal technology Co.
Modeling, grouping, dosing methods:
a mouse model of TAC-aortic arch constriction-induced chronic heart failure was established: after the mice were anesthetized by intraperitoneal injection of amifostine (0.2 g/kg), the mice were intubated and connected to a respirator. Dehairing in the operation area, opening downwards from the upper fossa of the sternum to the second rib, placing 6-0 silk thread at the aortic arch between the brachiocephalic trunk and the left common carotid artery, knotting around the aortic arch under the condition of placing 27G flat head needles in parallel with the aortic arch, removing the flat head needles, and closing the thoracic cavity. The Sham group was identical to the TAC group except for the ligation step.
Mice were divided into Sham, heart failure and Spexin active polypeptide treatment groups, labeled Sham, TAC and tac+spx, respectively. Each group of mice was given an intraperitoneal injection of 0.1ml of physiological saline or Spexin, at a dose of 70 μg/kg per day, for 8 weeks on model and treatment, starting on the day of surgery.
The individual groups of mouse cardiomyocytes were isolated and each group was tested for calcium transients and resting calcium levels, as in example 1.
FIG. 5 is a graph comparing the amplitude of calcium transients in cardiomyocytes for each group of mice; FIG. 6 is a graph comparing the calcium transient time profiles of cardiomyocytes in mice of each group; as shown in fig. 5 and 6, the TAC group mice had a reduced magnitude of calcium transients compared to Sham group, and the tac+spx group mice had a significantly increased magnitude of calcium transients compared to TAC group.
FIG. 7 is a graph showing the comparison of time constants of calcium decline in myocardial cells of mice in each group; as shown in fig. 7, the time course of calcium decline in the myocardial cells of mice in the TAC group was prolonged compared to Sham group, and the time course of calcium decline in the myocardial cells of mice in the tac+spx group was significantly reduced compared to TAC group.
FIG. 8 is a representative picture of the Fluo-3 staining of cardiomyocytes in each group of mice; FIG. 9 is a graph comparing resting calcium levels of cardiomyocytes in mice of each group; as shown in fig. 8 and 9, the mouse cardiomyocyte resting calcium level in the TAC group was increased compared to the Sham group, and the mouse cardiomyocyte resting calcium level in the tac+spx group was significantly decreased compared to the TAC group.
FIG. 10 is a representative graph of heart ultrasound test of each group of mice, FIG. 11 is a comparative graph of LVEF test results of each group of mice, FIG. 12 is a comparative graph of LVFS test results of each group of mice, and FIG. 13 is a comparative graph of survival curves of each group of mice; as shown in fig. 10 to 13, TAC mice LVEF and LVFS decreased compared to Sham group, suggesting a decrease in systole function; exogenous supplementation with Spexin restored mice LVEF and LVFS and reduced mortality.
The experimental result proves that the Spexin active polypeptide can enhance the contractility of cardiac muscle cells, increase the calcium in the cardiac muscle cells, relieve the imbalance of the calcium steady state of the cardiac muscle cells during chronic heart failure, improve the heart contractility, further improve the prognosis of heart failure mice, and is expected to be a safe and effective medicament for preventing and treating heart failure.
Claims (10)
- Use of a spexin active polypeptide for the preparation of a medicament for enhancing myocardial contractility.
- 2. The use of a Spexin active polypeptide according to claim 1, wherein the Spexin active polypeptide has an amino acid sequence of NWTPQAMLYLKGAQ.
- 3. The use of a Spexin active polypeptide according to claim 1 or 2 for the preparation of a medicament for enhancing myocardial contractility, wherein the medicament for enhancing myocardial contractility comprises the Spexin active polypeptide as the sole active ingredient or one of the active ingredients.
- 4. The use of a Spexin active polypeptide according to claim 3 in the manufacture of a medicament for enhancing myocardial contractility, wherein the Spexin active polypeptide is present in the medicament for enhancing myocardial contractility in an amount of 0.1wt% to 99wt%.
- 5. The use of a Spexin active polypeptide according to claim 4 for the manufacture of a medicament for enhancing myocardial contractility, wherein the medicament for enhancing myocardial contractility further comprises pharmaceutically acceptable excipients and/or carriers.
- 6. The use of a Spexin active polypeptide according to claim 5 for the manufacture of a medicament for increasing myocardial contractility in a mammal.
- 7. The use of a Spexin active polypeptide according to claim 6 for the manufacture of a medicament for increasing myocardial contractility, wherein the medicament for increasing myocardial contractility is in a parenteral dosage form, in particular an injectable dosage form.
- 8. The use of a Spexin active polypeptide according to claim 7 for the manufacture of a medicament for increasing myocardial contractility, wherein the medicament for increasing myocardial contractility comprises a medicament for treating heart failure caused by a heart failure-associated condition and a medicament for treating complications associated with heart failure.
- 9. The use of a Spexin active polypeptide according to claim 8 for the manufacture of a medicament for increasing myocardial contractility, wherein the heart failure-associated condition comprises coronary heart disease, hypertension, valvular disease, myocarditis, cardiomyopathy, arrhythmia, metabolic disease, tumor and/or a tumor treatment-associated cardiac disease, or a combination thereof.
- 10. The use of a Spexin active polypeptide according to claim 9 for the manufacture of a medicament for increasing myocardial contractility, wherein the metabolic disorder comprises: diabetes, dyslipidemia, thyroid disorders, hyperuricemia, metabolic syndrome, or a combination thereof.
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| CN202410024869.3A CN117815360A (en) | 2024-01-08 | 2024-01-08 | Application of Spexin active polypeptide in preparation of medicines for enhancing myocardial contractility |
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| CN202410024869.3A CN117815360A (en) | 2024-01-08 | 2024-01-08 | Application of Spexin active polypeptide in preparation of medicines for enhancing myocardial contractility |
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