Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
Exp Cell Res. 2022 Aug 15;417(2):113213. doi: 10.1016/j.yexcr.2022.113213. Epub 2022 May 23.
The impairment of the coronary microcirculatory barrier caused by acute myocardial infarction (AMI) is closely related to poor prognosis. Recently, pigment epithelial-derived factor (PEDF) has been proven to be a promising cardiovascular protective drug. In this study, we demonstrated the protective role of PEDF in endothelial tight junctions (TJs) and the vascular barrier in AMI.
2, 3, 5-triphenyltetrazolium chloride (TTC), echocardiography and immunofluorescence staining were used to observe the size of infarcted myocardium area and cardiac function in myocardial tissue, and the distribution of TJ proteins in human coronary endothelial cells (HCAEC). Dextran leakage assay and Transwell were used to assess the extent of vascular and HCAEC leakage. Polymerase chain reaction (PCR) and Western blot were used to detect TJ-related mRNA and protein, and signaling pathway protein expression.
PEDF effectively reduced the infarction area and improved cardiac function in AMI rats, and lowered the leakage in AMI rats' angiocarpy and oxygen-glucose deprivation (OGD)-treated HCAEC. Furthermore, PEDF upregulated the expression of TJ mRNA and proteins in vivo and vitro. Mechanistically, PEDF inhibited the expression of phosphorylated low-density lipoprotein receptor-related protein 6 (p-LRP6) and active β-catenin under OGD, thus suppressing the activation of the classical Wnt pathway.
These novel findings demonstrated that PEDF maintained the expression of TJ proteins and endothelial barrier integrity by inhibiting the classical Wnt pathway during AMI.
急性心肌梗死（AMI）引起的冠状动脉微循环屏障损伤与预后不良密切相关。最近，色素上皮衍生因子（PEDF）已被证明是一种有前途的心血管保护药物。在这项研究中，我们证明了 PEDF 在 AMI 中内皮紧密连接（TJ）和血管屏障中的保护作用。
使用 2,3,5-三苯基四氮唑氯化物（TTC）、超声心动图和免疫荧光染色观察心肌组织中梗死心肌面积和心功能，以及 TJ 蛋白在人冠状动脉内皮细胞（HCAEC）中的分布。葡聚糖渗漏测定和 Transwell 用于评估血管和 HCAEC 渗漏的程度。聚合酶链反应（PCR）和 Western blot 用于检测 TJ 相关的 mRNA 和蛋白以及信号通路蛋白表达。
PEDF 有效减少了 AMI 大鼠的梗死面积，改善了心功能，并降低了 AMI 大鼠血管和缺氧/葡萄糖剥夺（OGD）处理的 HCAEC 的渗漏。此外，PEDF 在体内和体外均上调了 TJ mRNA 和蛋白的表达。在机制上，PEDF 抑制了 OGD 下磷酸化低密度脂蛋白受体相关蛋白 6（p-LRP6）和活性 β-连环蛋白的表达，从而抑制了经典 Wnt 通路的激活。
这些新发现表明，PEDF 通过抑制经典 Wnt 通路在 AMI 期间维持 TJ 蛋白的表达和内皮屏障的完整性。
