Shengmai-Yin resists myocardial ischemia reperfusion injury by inhibiting K27 ubiquitination of absent in melanoma 2

IF 5.4 2区医学 Q1 CHEMISTRY, MEDICINAL Journal of ethnopharmacology Pub Date : 2025-04-09 Epub Date: 2025-02-24 DOI:10.1016/j.jep.2025.119553

Xiaojin Xu , Yuanyi Wang , Ke Pei , Chenhan Mao , Fei Fang , Tiantong Zhou , Meng Zhang , Pei-Na Meng , Zilun Wei , Chang Liu , Yang Dai , Rui Yin , Zhaoyang Chen , Xindong Wang

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Abstract

Ethnopharmacological relevance

Myocardial ischemia-reperfusion (I/R) injury stands as a significant contributor to cardiovascular disease. Shengmai-Yin (SMY), a traditional Chinese medicine, is widely used in myocardial infarct treatment. However, the specific mechanism of SMY in treating myocardial I/R injury is currently limited.

Aim of study

The study aimed to investigate the therapeutic efficacy of SMY in addressing myocardial I/R injury and elucidate its specific mechanisms.

Materials and methods

The active components of SMY were quantified using Ultra-high performance liquid chromatography-MS/MS (UPLC-MS/MS). Sprague-Dawley (SD) rats were treated with SMY post-I/R model establishment. Cardiac injury was assessed by heart weight to body weight ratio. Left ventricular function and infarct volume were evaluated using ultrasound cardiography and TTC staining. Tissue lesions were examined via hematoxylin-eosin (HE) and Sirius Red staining. Co-Immunoprecipitation (Co-IP) technology explored absent in melanoma 2 (AIM2) and K27 Ubiquitination Modification (K27-Ub) interactions. Immunofluorescence staining detected Apoptosis-associated Speck-like Protein containing a CARD (ASC) and AIM2 co-localization. Adeno-associated Virus (AAV) was used to upregulate AIM2 levels, while Shikonin was used to downregulate AIM2, to explore its roles in SMY's therapeutic effects on I/R injury.

Results

SMY can reduce infarct size and enhance cardiac function. Furthermore, SMY can inhibit tissue fibrosis. Fibrosis markers and proinflammatory factors were reduced after SMY treatment. Serum levels of Lactate Dehydrogenase (LDH) and Creatine Kinase -MB (CK-MB) were also decreased. Mechanistically, SMY inhibits the activation of the AIM2 inflammasome by downregulating the K27 ubiquitination of AIM2. Overexpression of AIM2 reversed the anti-I/R effect of SMY, suggesting that AIM2 plays a crucial role in I/R injury. The AIM2 inhibitor counteracts the therapeutic effect of SMY.

Conclusion

SMY inhibits the K27 ubiquitination modification of AIM2 and inhibits the activation of AIM2 inflammasomes after myocardial I/R injury.

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生脉饮通过抑制黑色素瘤中缺失的K27泛素化而抵抗心肌缺血再灌注损伤2。

民族药理学相关性：心肌缺血再灌注（I/R）损伤是心血管疾病的重要诱因。生脉饮（SMY）是一种中药，广泛用于治疗心肌梗死。然而，SMY治疗心肌I/R损伤的具体机制目前尚不清楚。研究目的：探讨SMY治疗心肌I/R损伤的疗效，并阐明其具体机制。材料与方法：采用超高效液相色谱-质谱联用技术（UPLC-MS/MS）对SMY有效成分进行定量分析。spague - dawley （SD）大鼠在i /R模型建立后给予SMY治疗。以心重与体重比评价心脏损伤程度。采用超声心动图和TTC染色评价左心室功能和梗死面积。苏木精-伊红（HE）和天狼星红染色检查组织病变。共同免疫沉淀（Co-IP）技术探索缺席黑色素瘤2 （AIM2）和K27泛素化修饰（K27- ub）的相互作用。免疫荧光染色检测到含有CARD （ASC）和AIM2共定位的凋亡相关斑点样蛋白。采用腺相关病毒（Adeno-associated Virus， AAV）上调AIM2水平，紫草素下调AIM2水平，探讨其在SMY治疗I/R损伤中的作用。结果：SMY能缩小梗死面积，增强心功能。此外，SMY还能抑制组织纤维化。SMY治疗后纤维化指标和促炎因子降低。血清乳酸脱氢酶（LDH）和肌酸激酶-MB （CK-MB）水平也降低。机制上，SMY通过下调AIM2的K27泛素化抑制AIM2炎性体的激活。AIM2过表达逆转了SMY的抗I/R作用，提示AIM2在I/R损伤中起关键作用。AIM2抑制剂抵消了SMY的治疗效果。结论：SMY可抑制心肌I/R损伤后AIM2的K27泛素化修饰，抑制AIM2炎症小体的活化。

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来源期刊

Journal of ethnopharmacology 医学-全科医学与补充医学

CiteScore

10.30

自引率

5.60%

发文量

967

审稿时长

77 days

期刊介绍： The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.