CN115463134B - 一种sirt2特异性抑制剂ak-1的应用 - Google Patents
一种sirt2特异性抑制剂ak-1的应用 Download PDFInfo
- Publication number
- CN115463134B CN115463134B CN202210355971.2A CN202210355971A CN115463134B CN 115463134 B CN115463134 B CN 115463134B CN 202210355971 A CN202210355971 A CN 202210355971A CN 115463134 B CN115463134 B CN 115463134B
- Authority
- CN
- China
- Prior art keywords
- sirt2
- inhibitor
- myocardial infarction
- heart
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 39
- 102000000477 Sirtuin 2 Human genes 0.000 title claims abstract description 38
- 108010041216 Sirtuin 2 Proteins 0.000 title claims abstract description 38
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 25
- 230000010016 myocardial function Effects 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims 2
- 229940079593 drug Drugs 0.000 abstract description 13
- 238000011282 treatment Methods 0.000 abstract description 8
- 238000007634 remodeling Methods 0.000 abstract description 6
- 239000013589 supplement Substances 0.000 abstract description 3
- 206010028594 Myocardial fibrosis Diseases 0.000 abstract 1
- 230000002107 myocardial effect Effects 0.000 abstract 1
- 206010016654 Fibrosis Diseases 0.000 description 8
- 230000004761 fibrosis Effects 0.000 description 8
- 210000004351 coronary vessel Anatomy 0.000 description 7
- 230000004217 heart function Effects 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 230000000747 cardiac effect Effects 0.000 description 6
- 206010061216 Infarction Diseases 0.000 description 5
- 230000007574 infarction Effects 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- 208000000435 Heart Rupture Diseases 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 210000005240 left ventricle Anatomy 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000002592 echocardiography Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 238000010837 poor prognosis Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102100039869 Histone H2B type F-S Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101001035372 Homo sapiens Histone H2B type F-S Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 102000011990 Sirtuin Human genes 0.000 description 1
- 108050002485 Sirtuin Proteins 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 210000003540 papillary muscle Anatomy 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种SIRT2特异性抑制剂AK‑1的应用,属于生物医药技术领域。本发明提供SIRT2抑制剂AK‑1在制备预防心梗后心脏破裂,改善心梗后心脏重构,改善心梗后心功能以及改善心梗后纤维化水平的药物上的应用;为SIRT2抑制剂AK‑1应用于临床,治疗心肌梗死后心脏重构提供理论依据;SIRT2抑制剂是对既往传统的心肌梗死治疗的重要补充,可以延缓心脏不良重构进展,提高患者生活质量。
Description
技术领域
本发明涉及一种SIRT2特异性抑制剂AK-1的应用,属于生物医药技术领域。
背景技术
心肌梗死是由于冠状动脉部分或完全闭塞导致部分心肌因严重的持久性缺血缺氧而发生局部坏死。流行病学研究显示,目前我国心血管疾病患者超过2.9亿,其中冠心病患者超过1100万,50%的心血管疾病死亡是由心肌梗死引起。随着溶栓方案的不断完善,以及介入治疗技术的快速发展,心肌梗死病死率得到了一定的控制,但其全球罹患率仍居高不下。心肌梗死后产生的不良心脏重构与心脏破裂、心力衰竭、心律失常的发生以及患者不良预后具有很强的相关性。因此,心肌梗死后的心脏重构一直是心血管疾病领域研究的重点,如何促进受损心肌愈合和预防梗死后不良心脏重构显得尤为重要。
Sirtuin蛋白家族是组蛋白和非组蛋白蛋白的III类烟酰胺腺嘌呤二核苷酸依赖性脱乙酰酶家族。SIRT2广泛的在组织中表达,特别是在心脏组织中。本发明应用左冠状动脉结扎模型,通过对生存率、心脏破裂率、心功能改变、纤维化严重程度等指标检测SIRT2特异性抑制剂AK-1对心肌梗死后心脏重构的治疗作用,为SIRT2抑制剂AK-1应用于临床治疗心肌梗死后心脏重构提供理论依据。
发明内容
本发明的目的是为解决SIRT2抑制剂AK-1在心血管疾病中如何应用的技术问题。
为达到解决上述问题的目的,本发明所采取的技术方案是提供SIRT2抑制剂在制备预防心梗后心脏破裂的药物上的应用。
优选地,所述SIRT2抑制剂为AK-1。
本发明提供SIRT2抑制剂在制备改善心梗后心脏重构的药物上的应用。
优选地,所述SIRT2抑制剂为AK-1。
本发明提供SIRT2抑制剂在制备改善心梗后心功能的药物上的应用。
优选地,所述SIRT2抑制剂为AK-1。
本发明提供SIRT2抑制剂在制备改善心梗后纤维化水平的药物上的应用。
优选地,所述SIRT2抑制剂为AK-1。
相比现有技术,本发明具有如下有益效果:
SIRT2特异性抑制剂在心肌梗死后心脏重构中的调节作用尚未有报道,本发明通过给予左冠状动脉结扎手术后的小鼠SIRT2抑制剂AK-1,可以有效提高心功能和减轻纤维化,改善梗死后心脏的不良重构,为SIRT2抑制剂AK-1应用于临床,治疗心肌梗死后心脏重构提供理论依据。SIRT2抑制剂是对既往传统的心肌梗死治疗如ACEI\ARB、beta受体抑制剂等治疗的重要补充,可以延缓心脏不良重构进展,提高患者生活质量。
附图说明
图1为对照组和药物治疗组随术后时间的生存率变化曲线图。
图2为对照组和药物治疗组在术后不同时间的心脏射血分数比较图。
图3为对照组和药物治疗组在术后2周心脏梗死面积和纤维化情况图。
具体实施方式
为使本发明更明显易懂,兹以优选实施例,并配合附图作详细说明如下:
如图1-3所示,本发明所采取的技术方案是提供SIRT2抑制剂在制备预防心梗后心脏破裂的药物上的应用;所述SIRT2抑制剂为AK-1。
本发明提供SIRT2抑制剂在制备改善心梗后心脏重构的药物上的应用;所述SIRT2抑制剂为AK-1。
本发明提供SIRT2抑制剂在制备改善心梗后心功能的药物上的应用;所述SIRT2抑制剂为AK-1。
本发明提供SIRT2抑制剂在制备改善心梗后纤维化水平的药物上的应用;所述SIRT2抑制剂为AK-1。
心脏重构是冠心病和心肌梗死预后不良的重要原因。在传统标准化治疗如ACEI\ARB、beta受体抑制剂等的基础上,本发明的研究表明SIRT2抑制剂可以有效降低心梗后心脏破裂风险,改善心脏不良重构,为SIRT2抑制剂应用于临床治疗心肌梗死后心脏重构提供理论依据。SIRT2抑制剂是对既往传统治疗的重要补充,可以延缓心脏不良重构进展,改善患者预后。
实施例
1)实验动物及动物模型制备:
选用SPF级雄性C57BL/6小鼠(购自上海杰思捷实验动物有限公司),周龄为8-10周,体重20-25g,给予左冠状动脉结扎手术(0.15%-0.2%异氟烷经氧合后呼吸麻醉、固定、脱毛并剪开胸前区皮肤,钝性分离胸大肌及胸小肌,持针器轻微戳破胸腔后旋转加压,顺势将心脏挤出后迅速结扎冠脉左前降支,结扎完成后立即关胸),构建心肌梗死模型。并将小鼠分为两组,对照组第一周每日腹腔注射生理盐水200ul,药物处理组第一周每日腹腔注射200ul AK-1药物(100μM)。左冠状动脉结扎手术后14天处死取材。
如图1所示为对照组和药物治疗组随术后时间的生存率变化曲线图。从图1中可得出:药物治疗组的生存率明显优于对照组。
2)超声心动图评价小鼠心功能:
检测超声心动图,探头频率为30MHz。具体为异氟烷气麻动物后,当小鼠的心率保持在450-500次/分钟时记录M-mode图像。釆集胸骨旁长轴切面、心尖四腔切面B-Mode图像。取胸骨旁左室短轴,2D超声示左室短轴切面,在乳头肌水平应用M型超声记录左心室运动情况。功能学指标包括:左室射血分数(LVEF)。比较各组小鼠心脏形态及功能变化。所有测量值均为连续5个心动周期的平均值,由3名经验丰富的技术人员进行。
如图2所示,图2中Sham组为假手术组,MI-Con为对照组,MI-AK-1为药物治疗组;从图2中显示术后不同时间,MI-AK-1药物治疗组的心功能指标明显优于MI-Con对照组。
结果显示:药物处理组小鼠心功能指标明显改善。
3)取材:
左冠状动脉结扎手术后2周后处死小鼠,取心脏,比较2组之间心脏梗死面积和纤维化情况。如图3所示;图3中MI-Con为对照组,MI-AK-1为药物治疗组;
结果发现:药物处理组MI-AK-1组心脏梗死面积和纤维化水平显著低于对照组MI-Con组。
结论:基于本发明的研究结果,AK-1可以明显改善小鼠心肌梗死后心功能和纤维化,为SIRT2特异性抑制剂应用于临床,治疗心肌梗死后心脏重构提供理论依据,同时也为心肌梗死后心脏重构的治疗提供新的靶点。
以上所述,仅为本发明的较佳实施例,并非对本发明任何形式上和实质上的限制,应当指出,对于本技术领域的普通技术人员,在不脱离本发明的前提下,还将可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。凡熟悉本专业的技术人员,在不脱离本发明的精神和范围的情况下,当可利用以上所揭示的技术内容而做出的些许更动、修饰与演变的等同变化,均为本发明的等效实施例;同时,凡依据本发明的实质技术对上述实施例所作的任何等同变化的更动、修饰与演变,均仍属于本发明的技术方案的范围内。
Claims (2)
1.SIRT2抑制剂在制备改善心梗后心功能的药物上的应用,所述SIRT2抑制剂为AK-1,所述AK-1的化学结构式如下所示:
。
2.SIRT2抑制剂在制备改善心梗后纤维化水平的药物上的应用其特征在于,所述SIRT2抑制剂为AK-1,所述AK-1的化学结构式如下所示:
。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210355971.2A CN115463134B (zh) | 2022-04-06 | 2022-04-06 | 一种sirt2特异性抑制剂ak-1的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210355971.2A CN115463134B (zh) | 2022-04-06 | 2022-04-06 | 一种sirt2特异性抑制剂ak-1的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115463134A CN115463134A (zh) | 2022-12-13 |
CN115463134B true CN115463134B (zh) | 2024-03-01 |
Family
ID=84364683
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210355971.2A Active CN115463134B (zh) | 2022-04-06 | 2022-04-06 | 一种sirt2特异性抑制剂ak-1的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115463134B (zh) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080021063A1 (en) * | 2006-07-18 | 2008-01-24 | Kazantsev Aleksey G | Compositions and methods for modulating sirtuin activity |
-
2022
- 2022-04-06 CN CN202210355971.2A patent/CN115463134B/zh active Active
Non-Patent Citations (1)
Title |
---|
Development and Characterization of 3-(Benzylsulfonamido)benzamides as Potent and Selective SIRT2 Inhibitors;Mohammad A. Khanfar et al.;《European Journal of Medicinal Chemistry》;第76卷;第414-426页 * |
Also Published As
Publication number | Publication date |
---|---|
CN115463134A (zh) | 2022-12-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Bevans et al. | The systemic lesions of malignant rheumatoid arthritis | |
Van Wyk et al. | Periarteritis nodosa: A case of fatal exfoliative dermatitis resulting from Dilantin sodium sensitization | |
Miao et al. | Atrial hemangioma: a case report and review of the literature | |
Hassan et al. | Feline aortic thromboembolism: Presentation, diagnosis, and treatment outcomes of 15 cats | |
CA2552529C (en) | Use of ribose in recovery from anaesthesia | |
CN115463134B (zh) | 一种sirt2特异性抑制剂ak-1的应用 | |
Van Buchem et al. | Myxoma Cordis: Diagnosis Established Pre-operatively; Surgical Removal of the Tumour | |
Kay et al. | Surgical correction of severe mitral prolapse without mitral insufficiency but with pronounced cardiac arrhythmias | |
Candell et al. | Post-traumatic coronary occlusion and early left ventricular aneurysm | |
d'Sa et al. | Arteriovenous fistula after hair transplantation. | |
CN113425731B (zh) | 一种增效干细胞治疗心梗的药物及其应用 | |
Menzies | Coronary embolism with infarction in bacterial endocarditis | |
Li et al. | Vital organ involvement in Sweet's syndrome with myelodysplastic syndrome: a case report and literature review. | |
WO2023023995A1 (zh) | 一种防治心肌缺血后心功能衰竭的药物及其应用 | |
Harrison et al. | Perforation of interventricular septum after myocardial infarction | |
CN113855650B (zh) | 一种免疫代谢心梗贴片及其制备方法与应用 | |
Vacek et al. | Spontaneous dissection of the left anterior descending coronary artery in a male with survival | |
CN109223749A (zh) | 5- 溴-2-(α- 羟基戊基)苯甲酸钠盐在治疗心肌肥厚和心力衰竭中的药物用途 | |
CN110613525A (zh) | 一种慢性心衰急性加重型动物模型的制备方法 | |
Han et al. | Valve replacement for valvular heart disease with giant left ventricle | |
CN115998737B (zh) | 阿莫地喹在制备治疗压力负荷性心肌损伤的药物中的应用 | |
US20240108658A1 (en) | Synergistic stem cell-based medication for treating myocardial infarction and related application | |
CN110664794A (zh) | 氨基氧乙酸在制备预防或治疗心梗的药物中的应用 | |
CN116785435A (zh) | Ep3受体拮抗剂l-798106在制备预防心肌缺血再灌注损伤药物中的应用 | |
CN117503932A (zh) | Jun抑制剂在制备用于治疗射血分数保留的心衰的药物中的用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |