CN102188697B - Application of recombinant human Rho kinase to preparation of medicaments - Google Patents
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- CN102188697B CN102188697B CN201010117580.4A CN201010117580A CN102188697B CN 102188697 B CN102188697 B CN 102188697B CN 201010117580 A CN201010117580 A CN 201010117580A CN 102188697 B CN102188697 B CN 102188697B
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Abstract
The invention discloses application of recombinant human Rho kinase to preparation of medicaments. Recombinant human Rho-associated coiled-coil forming protein kinase (ROCK)1 fragment protein (RP1 for short) has the activity of the Rho kinase, so that corresponding substrates can be phosphorylated; the RP1 has the effect of contracting blood vessels, and the functional regulation effect of the blood vessels is related to the endothelium of the blood vessels, is blocked by a calcium channel blocking agent and is inhibited by Fasudil serving as an Rho kinase inhibitor; after entering bodies of animals in an injection mode, the RP1 can rise the blood pressure of the animals and has the characteristic of quick response; and the RP1 has the effect of accelerating the heart rate of the animals under the condition of providing high dose in the injection mode, and has the effect of improving the blood vessel function reduced due to various factors including disease factors. The RP1 can be applied to the preparation of medicaments for relieving, preventing and/or treating cardiovascular and cerebrovascular diseases or symptoms which are caused by various factors including disease factors and are related to the reduction of the blood vessel function.
Description
Technical field
The present invention relates to the application of recombinant human Rho kinases in preparing medicine.
Technical background
As everyone knows, diseases of cardiovascular and cerebrovascular systems becomes the most common class disease of the mankind, accounts for first of global mortality rate, becomes the most important disease that threatens human health and life.Along with the acceleration of China's expanding economy, aged tendency of population, the quickening of rhythm of life, in crowd, suffer from the cardiovascular disease showed increased such as hypertension, hyperlipidemia, heart failure, apoplexy, directly increased the weight of family and burden on society.
Micromolecule gtp binding protein is a kind of monomer G protein molecular playing a crucial role in cell function adjustment process.Rho is a kind of small molecular G protein, in inactivated state, changes activated state when GTP is combined into when GDP is combined, and in the signal conduction between mediation cells of vascular wall, plays an important role.1985, from sea hare, belong in (Aplysia) animal body and find that Rho gene is a homologous genes of Ras gene.Based on its 26S Proteasome Structure and Function, analyze, Rho superfamily can be divided into Rho, Rac and tri-subfamilies of Cdc42.Calcium ion is proved to be a crucial regulatory factor of cytoskeleton very early, and more and more evidence shows, Rho superfamily is the important factor of the adjusting cell function of another actin dependence.
Rho kinases (Rho-associated coiled-coil forming protein kinase, ROCK) has 2 hypotypes, i.e. ROCK1 and ROCK2, and they are all serine/threonine kinases.The prlmary structure of protein of 2 hypotypes has 65% homology, from N end, contain successively kinase catalytic domain, Rho binding structural domain, PH (pleckstrin homology) domain and cysteine enrichment domain, wherein the homology of catalyst structure domain is up to 92%.ROCK1 and ROCK2 are distributed widely in the most organs of body, and ROCK2 is rich content in brain, and ROCK1 is higher at the organ expression of Non nervous system, as heart, lung, skeletal muscle.In cell, ROCK2 is mainly arranged in endochylema, only has on a small quantity and is positioned on cell membrane.Research shows, the signal transduction pathway of Rho/ROCK mediation, the activities such as the division of cell, contraction, adhesion, migration, secretion are had to important regulative, as growth of smooth muscle cell contraction, Cytoskeleton, cell migration and proliferation and neuronic formation and aixs cylinder etc.
Up to now, we do not find recombinant human ROCK1 function fragment albumen and by various factors, are being comprised that vascular function that disease factor causes reduces the application relevant report of relevant cardiovascular and cerebrovascular disease and/or symptom.
Summary of the invention
One embodiment of the invention provide the recombinant human ROCK1 function fragment albumen (referred to as RP1) shown in SEQ ID NO:1 in preparation prevention, alleviation and/or the cardiovascular and cerebrovascular disease for the treatment of and/or the application in symptom medicine.Described cardiovascular and cerebrovascular disease and/or symptom can be that the vascular function that various diseases factor causes reduces relevant.
One embodiment of the invention provide the application of the recombinant human ROCK1 function fragment albumen shown in SEQ ID NO:1 in preparing vasoconstrictive medicine.Described vasoconstrictive effect is relevant to blood vessel endothelium, by calcium channel blocker, blocked, by Rho inhibitors of kinases, suppressed.Described calcium channel blocker is selected from nitrendipine, verapamil; Described Rho inhibitors of kinases is selected from fasudil.
One embodiment of the invention provide the recombinant human ROCK1 function fragment albumen shown in SEQ ID NO:1 to rise the application in hypertensive medicine in preparation.Described blood pressure is systolic pressure and diastolic pressure
One embodiment of the invention provide the application of the recombinant human ROCK1 function fragment albumen shown in SEQ ID NO:1 in the medicine of preparation quickening heart rate.
One embodiment of the invention provide the application of the recombinant human ROCK1 function fragment albumen shown in SEQ ID NO:1 in the medicine of preparation prevention, alleviation or treatment shock.
One embodiment of the invention also provide the application of the recombinant human ROCK1 function fragment albumen shown in SEQ ID NO:1 at inhibitor screening and in evaluating.
In the present invention, described prevention, alleviation and/or treatment comprise that by various factors vascular function that disease factor causes reduces relevant cardiovascular and cerebrovascular disease and/or symptom and is selected from RP1 and has Rho kinase activity and can make corresponding substrate phosphorylation; RP1 has vasoconstrictive effect, and this vascular function regulating action is relevant to blood vessel endothelium, by calcium channel blocker, blocked, by Rho inhibitors of kinases-fasudil, suppressed; Animal blood pressure show rapid-action feature can raise after entering in animal body in intravenous injection mode; While giving higher dosage with injection system, there is the effect of accelerating animal heart rate; Have and improve the effect that comprises the vascular function that disease factor reduces due to various factors.
The present invention also provides the method for measuring RP1 activity, and RP1 has serine/threonine kinase characteristic, makes the peptide substrate phosphorylations such as S6 (AKRRRLSSLRA) and consumes ATP, can detect the kinase activity of RP1 by measuring ATP content.Therefore RP1 of the present invention in application that can be at inhibitor screening and in evaluating, for example, carries out drug screening by the evaluation of RP1 enzymatic activity, assessing compound or the impact of other materials on enzymatic activity.
The present invention realizes by following technical solution: by clonal expression biology techniques, obtain RP1, utilize ROCK1 protein active evaluation system, the kinases biologic activity of confirmation RP1, by extracorporeal blood vessel ring strain, measure system, further observe RP1 to the reactive impact of normal rat aorta, judge that RP1 is to the contraction of isolated rat blood vessel and mechanism, be administered to RP1 and observe the impact of anesthetized rat blood pressure and heart rate and judge in preparation prevention, alleviate and/or treatment comprises that by various factors vascular function that disease factor causes reduces the application in the medicine of relevant cardiovascular and cerebrovascular disease or symptom.
Accompanying drawing explanation
The impact of Fig. 1 .Rho kinases specific inhibitor Y-27632 on RP1 activity.
Fig. 2 .RP1 is the complete and reactive impact of endothelium-denuded rat aorta on endothelium.
Fig. 3. endothelium-derived active substance is on the RP1 vasoactive impact of contracting.
Fig. 4. calcium channel blocker is on the RP1 vasoactive impact of contracting.
Fig. 5 .Rho inhibitors of kinases-fasudil is on the RP1 vasoactive impact of contracting.
Fig. 6. the lift-off value of the RP1 of various dose to anesthetized rat blood pressure.
The effect of Fig. 7 .RP1 rising anesthetized rat blood pressure.
Fig. 8. the impact of the RP1 of various dose on anesthetized rat heart rate.
The specific embodiment
Below in conjunction with the present invention, further illustrate RP1 and rise in vivo hypertensive pharmacological action and by various factors, comprise that vascular function that disease factor causes reduces the application of relevant cardiovascular and cerebrovascular disease in treatment.Following embodiment illustrates the present invention in more detail, is not any limitation of the invention.Below in conjunction with drawings and Examples, the application's patent is further illustrated.
The kinases bio-evaluation of embodiment 1:RP1.
The present embodiment has been identified the activity of RP1 by Kinase-Glo Luminescent Kinase Assay method.Reaction is carried out in 96 orifice plates of White-opalescent, adds 5 μ L kinase buffer liquid (25mmolL
-1tris-HCl, pH7.5,10mmolL
-1mgCl
2, 0.1mgmL
-1bSA), 10 μ L kinases, 10 μ L S6 (AKRRRLSSLRA) peptide substrates and 5 μ L ATP.Mix latter 37 ℃ and hatch certain hour, add 50 μ L Kinase-Glo reagent, room temperature 10min reads the relative light unit in each hole on SpectraMax M5.During reaction, add 10 μ molL
-1y-27632 (the kinase whose specific inhibitor of Rho), observe the activity that can it optionally suppress RP1, simultaneously with do not add kinase whose blank and add kinase whose positive control comparison, to judge the Rho kinases biologic activity of RP1 in embodiment 1.
Add kinase whose positive control and do not add kinase whose blank comparison, having significant difference, prompting RP1 has biologic activity.Add kinase whose positive control and the control wells comparison that adds Rho kinases selective depressant-Y-27632, there is significant difference, prove that Y-27632 energy specificity suppresses the Rho kinase activity of RP1, the results are shown in accompanying drawing 1.
The impact of embodiment 2:RP1 on anesthetized rat vascular reactivity.
Laboratory animal in the present embodiment is selected male SD rat (body weight 250～300g).After rat sacrificed by decapitation, take out rapidly thoracic aorta, be cut into the long vascular ring of 2～3mm, vascular ring is placed in and fills K-H liquid 10mL (37 ℃ of constant temperature, and continue to pass into the mist of 95% oxygen and 5% carbon dioxide) bath in, tension variation is transmitted and is recorded in BL-420S biological function experimental system.Vascular ring is at 1.2g tension stability 60min, during every 20min change K-H liquid 1 time.With 60mM KCl, stimulate vascular ring, vascular ring is shunk, reach amplitude peak afterflush 2 times, make vascular ring return to the state before stimulation, totally 2 times.Add 1 μ M norepinephrine, give the acetylcholine of 10 μ M after reaching maximum shrinkage amplitude, and measure its diastole amplitude.If it is complete that diastole amplitude is greater than 80% expression endothelium, show in operating process minimumly to the loss of vascular ring endothelium, endothelium integrity is good, for there being endothelium group; If not diastole or diastole amplitude are less than, 30% expression endothelial loss is large, and endothelial function is imperfect, for without endothelium group.Detect after endothelial function, rinse the state before extremely stimulating, then stablize 30min, further detect RP1 to the reactive impact of rat aorta.
1,3,10,30, the RP1 of 100 μ M cumulative concentrations causes without endothelium and has an interior cutaneous vessel narrowing of the ring (accompanying drawing 2), and its contraction is increased and strengthened with concentration, and is dose-effect relationship, it promotes the effect of vascular function significantly to depend on arterial endothelium, judges that RP1 comprises that by various factors vascular function that disease factor causes reduces pharmacological action and the application of relevant cardiovascular and cerebrovascular disease on the reactive impact of rat aorta and in treatment.
Embodiment 3: various endothelium-derived active substances are on the RP1 vasoactive impact of contracting.
Tension detection uses vascular ring preparation method with embodiment 3.
The present embodiment by adding nitric oxide synthase inhibitors L-NAME (100 μ M) in reaction system, cyclooxygenase-2 inhibitors indomethacin (5 μ M), guanylate cyclase inhibitor methylene blue (10 μ M), the RP1 that adds cumulative concentration after preincubate 20min, observes endothelium-derived active substance to the RP1 vasoactive impact of contracting.L-NAME can significantly strengthen RP1 contracting blood vessel function (accompanying drawing 3).The regulating action to vascular function of judging RP1 has endothelium-dependent relaxation.
Embodiment 4: calcium channel blocker is on the RP1 vasoactive impact of contracting.
Tension detection uses vascular ring preparation method with embodiment 3.
The present embodiment by adding L-type calcium channel blocker nitrendipine (nitrendipine in reaction system, 1mM), verapamil (verapamil, 10mM), after preincubate 20min, add the RP1 of cumulative concentration, observe calcium channel to the RP1 vasoactive impact of contracting.Judge whether RP1 regulates vascular reactivity by calcium channel.Nitrendipine, verapamil can significantly reduce RP1 contracting blood vessel function (accompanying drawing 4), and the contracting blood vessel character that RP1 is described is the open effect producing by calcium channel, and the effect of RP1 adjusting vascular function can be by calcium channel blocker institute antagonism.
Embodiment 5: fasudil is on the vasoactive impact of contracting of restructuring ROCK1 albumen.
Tension detection uses vascular ring preparation method with embodiment 3.
The present embodiment, by add Rho inhibitors of kinases fasudil (10 μ M) in reaction system, adds the restructuring ROCK1 albumen of cumulative concentration after preincubate 20min, observe fasudil to the vasoactive impact of contracting of restructuring ROCK1 albumen.Fasudil can significantly reduce restructuring ROCK1 albumen contracting blood vessel function (accompanying drawing 5).The contracting effect of confirming restructuring ROCK1 albumen is suppressed by fasudil.
The effect of embodiment 6:RP1 to rat blood pressure and heart rate.
In rat body, blood pressure determination ambient temperature is controlled at 18-25 ℃, and humidity is controlled between 45%-60%, Indoor Natural light.SD rat 250 ± 20g, with urethane (1.25g/kg) intraperitoneal injection of anesthesia, is fixed on operating-table.Separated rat femoral, femoral arteriography is connected with BL-420S biological function experimental system through pressure transducer, traces rat artery systolic pressure and diastolic pressure; Limbs II is led and is connect BL-420S biological function experimental system, and recording ecg carries out electrocardiography, recorded heart rate.After postoperative stable 10min, tail vein is given and RP1 (0.02mg/kg, 0.1mg/kg, 0.5mg/kg), continuous sampling 1h after administration.Observe the variation of RP1 to rat blood pressure and heart rate.Result shows, RP1 significantly raise systolic pressure and the diastolic pressure (accompanying drawing 6) of anesthetized rat, and its boosting has rapid-action feature, inject within latter 1 minute and just can reach the object of boosting (accompanying drawing 7), 0.5mg/kg dosage group has the effect (accompanying drawing 8) of accelerating anesthetized rat heart rate.Judge the effect of RP1 rising rat blood pressure and accelerate the effect of rat heart rate and in pharmacological action and the application for the treatment of shock property disease and/or symptom.
In sum, RP1 has Rho kinase activity and can make corresponding substrate phosphorylation; Have vasoconstrictive effect, this vascular function regulating action is relevant to blood vessel endothelium, by calcium channel blocker, blocked, by Rho inhibitors of kinases-fasudil, suppressed; Animal blood pressure show rapid-action feature can raise after entering in animal body in intravenous injection mode; While giving higher dosage with injection system, there is the effect of accelerating animal heart rate; Have and improve because various factors comprises the vascular function that disease factor reduces.RP1 has good applicating and exploitation prospect, can be applicable to alleviate, prevents and/or treats by various factors and comprise that vascular function that disease factor causes reduces the preparation of the medicine of relevant cardiovascular and cerebrovascular disease or symptom.
Sequence table
SEQUENCE LISTING
<110> institute of Materia Medica,Chinese Academy of Medical Sciences
The application of <120> recombinant human Rho kinases in preparing medicine
<130>P10002
<160>1
<170>PatentIn version 3.3
<210>1
<211>541
<212>PRT
<213> recombinant human ROCK1 function fragment albumen
<400>1
Thr Gly Asp Ser Phe Glu Thr Arg Phe Glu Lys Met Asp Asn Leu Leu
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Arg Asp Pro Lys Ser Glu Val Asn Ser Asp Cys Leu Leu Asp Gly Leu
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Asp Ala Leu Val Tyr Asp Leu Asp Phe Pro Ala Leu Arg Lys Asn Lys
35 40 45
Asn Ile Asp Asn Phe Leu Ser Arg Tyr Lys Asp Thr Ile Asn Lys Ile
50 55 60
Arg Asp Leu Arg Met Lys Ala Glu Asp Tyr Glu Val Val Lys Val Ile
65 70 75 80
Gly Arg Gly Ala Phe Gly Glu Val Gln Leu Val Arg His Lys Ser Thr
85 90 95
Arg Lys Val Tyr Ala Met Lys Leu Leu Ser Lys Phe Glu Met Ile Lys
100 105 110
Arg Ser Asp Ser Ala Phe Phe Trp Glu Glu Arg Asp Ile Met Ala Phe
115 120 125
Ala Asn Ser Pro Trp Val Val Gln Leu Phe Tyr Ala Phe Gln Asp Asp
130 135 140
Arg Tyr Leu Tyr Met Val Met Glu Tyr Met Pro Gly Gly Asp Leu Val
145 150 155 160
Asn Leu Met Ser Asn Tyr Asp Val Pro Glu Lys Trp Ala Arg Phe Tyr
165 170 175
Thr Ala Glu Val Val Leu Ala Leu Asp Ala Ile His Ser Met Gly Phe
180 185 190
Ile His Arg Asp Val Lys Pro Asp Asn Met Leu Leu Asp Lys Ser Gly
195 200 205
His Leu Lys Leu Ala Asp Phe Gly Thr Cys Met Lys Met Asn Lys Glu
210 215 220
Gly Met Val Arg Cys Asp Thr Ala Val Gly Thr Pro Asp Tyr Ile Ser
225 230 235 240
Pro Glu Val Leu Lys Ser Gln Gly Gly Asp Gly Tyr Tyr Gly Arg Glu
245 250 255
Cys Asp Trp Trp Ser Val Gly Val Phe Leu Tyr Glu Met Leu Val Gly
260 265 270
Asp Thr Pro Phe Tyr Ala Asp Ser Leu Val Gly Thr Tyr Ser Lys Ile
275 280 285
Met Asn His Lys Asn Ser Leu Thr Phe Pro Asp Asp Asn Asp Ile Ser
290 295 300
Lys Glu Ala Lys Asn Leu Ile Cys Ala Phe Leu Thr Asp Arg Glu Val
305 310 315 320
Arg Leu Gly Arg Asn Gly Val Glu Glu Ile Lys Arg His Leu Phe Phe
325 330 335
Lys Asn Asp Gln Trp Ala Trp Glu Thr Leu Arg Asp Thr Val Ala Pro
340 345 350
Val Val Pro Asp Leu Ser Ser Asp Ile Asp Thr Ser Asn Phe Asp Asp
355 360 365
Leu Glu Glu Asp Lys Gly Glu Glu Glu Thr Phe Pro Ile Pro Lys Ala
370 375 380
Phe Val Gly Asn Gln Leu Pro Phe Val Gly Phe Thr Tyr Tyr Ser Asn
385 390 395 400
Arg Arg Tyr Leu Ser Ser Ala Asn Pro Asn Asp Asn Arg Thr Ser Ser
405 410 415
Asn Ala Asp Lys Ser Leu Gln Glu Ser Leu Gln Lys Thr Ile Tyr Lys
420 425 430
Leu Glu Glu Gln Leu His Asn Glu Met Gln Leu Lys Asp Glu Met Glu
435 440 445
Gln Lys Cys Arg Thr Ser Asn Ile Lys Leu Asp Lys Ile Met Lys Glu
450 455 460
Leu Asp Glu Glu Gly Asn Gln Arg Arg Asn Leu Glu Ser Thr Val Ser
465 470 475 480
Gln Ile Glu Lys Glu Lys Met Leu Leu Gln His Arg Ile Asn Glu Tyr
485 490 495
Gln Arg Lys Ala Glu Gln Glu Asn Glu Lys Arg Arg Asn Val Glu Asn
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Glu Val Ser Thr Leu Lys Asp Gln Leu Glu Asp Leu Lys Lys Val Ser
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Gln Asn Ser Gln Leu Ala Asn Glu Lys Leu Ser Gln Leu
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Claims (4)
- Recombinant human ROCK1 function fragment albumen shown in 1.SEQ ID NO:1 is alleviated and/or treats the application in cardiovascular and cerebrovascular diseases medicament in preparation, it is characterized in that, described cardiovascular and cerebrovascular disease is selected from shock, and by vascular function, is reduced relevant.
- Recombinant human ROCK1 function fragment albumen shown in 2.SEQ ID NO:1 is alleviated and/or treats the application in shock drug in preparation, it is characterized in that, described alleviation and/or treatment shock are relevant with vasoconstrictive.
- 3. according to the application of claim 2, it is characterized in that, described vasoconstrictive effect is relevant to blood vessel endothelium, can be blocked by calcium channel blocker, can be suppressed by Rho inhibitors of kinases.
- 4. according to the application of claim 3, it is characterized in that, described calcium channel blocker is selected from nitrendipine, verapamil; Described Rho inhibitors of kinases is selected from fasudil.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5906819A (en) * | 1995-11-20 | 1999-05-25 | Kirin Beer Kabushiki Kaisha | Rho target protein Rho-kinase |
| CN1233188A (en) * | 1996-08-12 | 1999-10-27 | 吉富制药株式会社 | Medicines comprising Rho kinase inhibitor |
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2010
- 2010-03-03 CN CN201010117580.4A patent/CN102188697B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5906819A (en) * | 1995-11-20 | 1999-05-25 | Kirin Beer Kabushiki Kaisha | Rho target protein Rho-kinase |
| CN1233188A (en) * | 1996-08-12 | 1999-10-27 | 吉富制药株式会社 | Medicines comprising Rho kinase inhibitor |
Non-Patent Citations (13)
| Title |
|---|
| Hiroaki S et al..Rho-kinase is an important therapeutic target in cardiovascular medicine.《Journal of the American heart association》.2005,第25卷(第9期),1767-1773. * |
| Liao JK et al..Rho kinase(ROCK) inhibitors.《J cardiovasc pharmacol》.2007,第50卷(第1期),17-24. * |
| Loirand G et al..Rho Kinases in cardiovascular physiology and pathophysiology.《Journal of the American heart association》.2006,第98卷第323页第1段，第328页右栏ROCKs and cardiovascular diseases和Rocks and Hypertension部分，图1，表2. * |
| Rho kinase(ROCK) inhibitors;Liao JK et al.;《J cardiovasc pharmacol》;20070731;第50卷(第1期);17-24 * |
| Rho Kinases in cardiovascular physiology and pathophysiology;Loirand G et al.;《Journal of the American heart association》;20060217;第98卷;第323页左栏第1段，第326页左栏ROCKs and vascular smooth muscle cell contraction部分，第328页右栏ROCKs and cardiovascular diseases和Rocks and Hypertension部分，图1，表2 * |
| RhoA-Rho kinase signaling mediates endothelium- and endoperoxide-dependent contractile activities characteristic of hypertensive vascular dysfunction;Steven G et al.;《Am J physiol heart circ physiol》;20100212;第298卷;H1391-H1405 * |
| Rho-kinase is an important therapeutic target in cardiovascular medicine;Hiroaki S et al.;《Journal of the American heart association》;20050707;第25卷(第9期);1767-1773 * |
| Steven G et al..RhoA-Rho kinase signaling mediates endothelium- and endoperoxide-dependent contractile activities characteristic of hypertensive vascular dysfunction.《Am J physiol heart circ physiol》.2010,第298卷H1391-H1405. * |
| Stockwell TB et al..Accession No:ACA06069，rho-associated protein kinase 1.《GenBank database》.2008,Features 和Origin部分. * |
| 宫丽丽等.心血管疾病治疗的新靶点――Rho激酶.《中国药学杂志》.2008,第43卷(第01期),1-3. * |
| 宫丽丽等.重组人Rho激酶的表达纯化及其活性检测.《医药导报》.2007,第26卷摘要部分. * |
| 心血管疾病治疗的新靶点――Rho激酶;宫丽丽等;《中国药学杂志》;20080108;第43卷(第01期);1-3 * |
| 重组人Rho激酶的表达纯化及其活性检测;宫丽丽等;《医药导报》;20071101;第26卷;摘要部分 * |
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