Shexiang Tongxin dropping pill ameliorates microvascular obstruction via downregulating ALOX12 after myocardial ischemia-reperfusion

IF 4.3 3区材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC

ACS Applied Electronic Materials Pub Date : 2024-08-22 DOI:10.1016/j.ijcard.2024.132481

Yuanhao Wu , Yanjun Lin , Bo Liu , Jingqing Ma , Yin Xiang , Yuepeng Wang , Shu Meng

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Abstract

Background

Microvascular dysfunction (MVD) is common in patients with myocardial infarction receiving reperfusion therapy and is associated with adverse cardiac prognosis. Accumulating evidence suggests a protective role of Shexiang Tongxin dropping pill (STDP) in MVD. However, the specific effects and the underlying mechanisms of STDP in the context of MVD after myocardial ischemia-reperfusion (IR) remains unclear.

Aims

We aimed to elucidate the role of STDP in MVD induced by IR and the potential mechanisms involved.

Methods

Mice were orally administered with STDP or normal saline for 5 days before receiving myocardial IR. Cardiac function and microvascular obstruction was measured. Proteomics and single-cell RNA sequencing was performed on mouse hearts. In vitro hyoxia/reoxygenation model was established on mouse cardiac microvascular endothelial cells (MCMECs).

Results

STDP improved cardiac function and decreased microvascular obstruction (MVO) in mice after myocardial IR. Proteomics identified ALOX12 as an important target of STDP. Single-cell RNA sequencing further revealed that downregulation of ALOX12 by STDP mainly occurred in endothelial cells. The involvement of ALOX12 in the effect of STDP on MVO was validated by manipulating ALOX12 via endothelial-specific adeno-associated virus transfection in vivo and in vitro. In vivo, overexpression of ALOX12 increased whereas knockdown of ALOX12 decreased MVO and thrombus formation. STDP treatment alleviated the detrimental effects of overexpression of ALOX12. In vitro, overexpression of ALOX12 increased endothelial cell inflammation and platelet adhesion to endothelial cells, which was abolished by STDP treatment.

Conclusion

Our findings suggest that STDP alleviates MVO after IR, with ALOX12 playing a crucial role.

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心肌缺血再灌注后，射香通脉滴丸通过下调ALOX12改善微血管阻塞。

背景：微血管功能障碍（MVD）在接受再灌注治疗的心肌梗死患者中很常见，并与心脏预后不良有关。越来越多的证据表明，沉香通心滴丸（STDP）对 MVD 有保护作用。目的：我们旨在阐明 STDP 在 IR 诱导的 MVD 中的作用及其潜在机制：方法：小鼠在接受心肌IR之前口服STDP或生理盐水5天。测量心功能和微血管阻塞情况。对小鼠心脏进行了蛋白质组学和单细胞 RNA 测序。在小鼠心脏微血管内皮细胞（MCMECs）上建立了体外缺氧/复氧模型：结果：STDP 改善了小鼠心肌梗死后的心功能，减少了微血管阻塞（MVO）。蛋白质组学发现 ALOX12 是 STDP 的一个重要靶点。单细胞 RNA 测序进一步发现，STDP 对 ALOX12 的下调主要发生在内皮细胞中。通过体内和体外内皮特异性腺相关病毒转染 ALOX12，验证了 ALOX12 参与 STDP 对 MVO 的影响。在体内，过表达 ALOX12 会增加 MVO 和血栓形成，而敲除 ALOX12 则会减少 MVO 和血栓形成。STDP 处理减轻了过表达 ALOX12 的有害影响。在体外，过表达 ALOX12 会增加内皮细胞炎症和血小板对内皮细胞的粘附，而 STDP 处理可消除这种现象：我们的研究结果表明，STDP 可减轻 IR 后的 MVO，其中 ALOX12 起着关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Applied Electronic Materials Multiple-

CiteScore

7.20

自引率

4.30%

发文量

567