Zhuang Qizhen, Chen Lu, Wu Wanqian, Wang Qing, Kang Chunmin, Xiong Yujuan, Huang Xianzhang
The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China.
Front Pharmacol. 2025 Mar 3;16:1538697. doi: 10.3389/fphar.2025.1538697. eCollection 2025.
Endothelial dysfunction-induced microcirculation impairment and the no-reflow phenomenon are the leading causes of cardiac ischemia/reperfusion (I/R) injury. There is an urgent need to elucidate the underlying mechanism of I/R-mediated endothelial dysfunction and to identify effective drugs for treatment. Scutellarin (SCU), a flavonoid compound, has been extensively studied because of its various pharmacological properties, including its potent protective effects on the cardiovascular system. However, the anti-endothelial dysfunction efficacy and mechanisms of action of SCU have not been investigated.
An I/R injury model was established using coronary artery ligation and release. An oxygen-glucose deprivation/oxygen-glucose resupply (OGD/OGR) approach was used to establish an I/R injury model. We evaluated the effects of SCU on endothelial dysfunction under I/R conditions, both and . SCU pretreatment promoted vasodilation and reperfusion of blood flow, inhibited myocardial injury and infarction, and improved cardiac function in I/R rats. Additionally, SCU inhibited cell membrane damage, reactive oxygen species (ROS) accumulation, inflammation, nitric oxide (NO) reduction, endothelin 1 (ET-1) elevation and increase in the expression levels of vascular endothelial growth factor (VEGF) and von willebrand factor (vWF) in endothelial cells. Mechanistically, SCU rescued the lysosomal flow and autophagic flux disrupted by I/R through upregulating cathepsin D (CTSD) levels. Knockdown of or treatment with the CTSD inhibitor pepstatin A (P.A) abrogated the protective effects of SCU on endothelial cells under I/R conditions.
We demonstrated that SCU, via upregulation of CTSD levels in endothelial cells, rescued autophagy-lysosomal function and alleviated I/R-mediated endothelial dysfunction. Thus, SCU is a potential therapeutic drug for the prevention and treatment of cardiac I/R injury.
内皮功能障碍引起的微循环障碍和无复流现象是心脏缺血/再灌注（I/R）损伤的主要原因。迫切需要阐明I/R介导的内皮功能障碍的潜在机制，并确定有效的治疗药物。灯盏花素（SCU）是一种黄酮类化合物，因其具有多种药理特性，包括对心血管系统的强大保护作用，而受到广泛研究。然而，SCU抗内皮功能障碍的疗效和作用机制尚未得到研究。
采用冠状动脉结扎和松开的方法建立I/R损伤模型。采用氧糖剥夺/氧糖再供应（OGD/OGR）方法建立I/R损伤模型。我们评估了SCU在I/R条件下对内皮功能障碍的影响。SCU预处理促进了I/R大鼠的血管舒张和血流再灌注，抑制了心肌损伤和梗死，并改善了心脏功能。此外，SCU抑制了内皮细胞膜损伤、活性氧（ROS）积累、炎症、一氧化氮（NO）减少、内皮素1（ET-1）升高以及血管内皮生长因子（VEGF）和血管性血友病因子（vWF）表达水平的增加。机制上，SCU通过上调组织蛋白酶D（CTSD）水平挽救了I/R破坏的溶酶体流动和自噬通量。敲低CTSD或用CTSD抑制剂胃蛋白酶抑制剂A（P.A）处理可消除SCU在I/R条件下对内皮细胞的保护作用。
我们证明，SCU通过上调内皮细胞中的CTSD水平，挽救了自噬-溶酶体功能，减轻了I/R介导的内皮功能障碍。因此，SCU是预防和治疗心脏I/R损伤的潜在治疗药物。
