Medical School Of Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China.
Medical School Of Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China; Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China.
Int J Cardiol. 2024 Dec 1;416:132481. doi: 10.1016/j.ijcard.2024.132481. Epub 2024 Aug 22.
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.
We aimed to elucidate the role of STDP in MVD induced by IR and the potential mechanisms involved.
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).
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.
Our findings suggest that STDP alleviates MVO after IR, with ALOX12 playing a crucial role.
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，与不良心脏预后相关。越来越多的证据表明麝香通心滴丸（STDP）在 MVD 中具有保护作用。然而，STDP 在心肌缺血再灌注（IR）后 MVD 中的具体作用和潜在机制尚不清楚。
本研究旨在阐明 STDP 在 IR 诱导的 MVD 中的作用及其潜在机制。
在接受心肌 IR 前，小鼠连续 5 天口服 STDP 或生理盐水。测量心功能和微血管阻塞。对小鼠心脏进行蛋白质组学和单细胞 RNA 测序。在体外建立缺氧/复氧模型，观察小鼠心脏微血管内皮细胞（MCMECs）的变化。
STDP 改善了心肌 IR 后小鼠的心脏功能，减少了微血管阻塞（MVO）。蛋白质组学鉴定 ALOX12 为 STDP 的一个重要靶点。单细胞 RNA 测序进一步表明，STDP 通过下调内皮细胞中的 ALOX12 发挥作用。通过体内和体外内皮特异性腺相关病毒转染来操纵 ALOX12，验证了 ALOX12 在 STDP 对 MVO 影响中的作用。体内，ALOX12 的过表达增加而敲低减少了 MVO 和血栓形成。STDP 处理缓解了 ALOX12 过表达的有害作用。在体外，ALOX12 的过表达增加了内皮细胞炎症和血小板黏附到内皮细胞，而 STDP 处理则消除了这种作用。
本研究结果表明，STDP 缓解了 IR 后的 MVO，ALOX12 发挥了关键作用。
