State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Division of Cardiovascular Medicine, University of Texas Health Science Center at Houston, Houston, TX, United States of America.
PLoS One. 2018 Jun 18;13(6):e0198403. doi: 10.1371/journal.pone.0198403. eCollection 2018.
Endothelial barrier function in the onset and Tongxinluo (TXL) protection of myocardial ischemia/reperfusion (I/R) injury, and TXL can induce the secretion of Angiopoietin-like 4 (Angptl4) in human cardiac microvascular endothelial cells during hypoxia/reoxygenation. We intend to demonstrate whether TXL can attenuate myocardial I/R injury in diabetes, characterized with microvascular endothelial barrier disruption, by induction of Angptl4-mediated protection of endothelial barrier integrity.
I/R injury was created by coronary ligation in ZDF diabetic and non-diabetic control rats. The animals were anesthetized and randomized to sham operation or I/R injury with or without the exposure to insulin, rhAngptl4, TXL, Angptl4 siRNA, and the PPAR-α inhibitor MK886. Tongxinluo, insulin and rhAngptl4 have the similar protective effect on diabetic hearts against I/R injury. In I/R-injured diabetic hearts, TXL treatment remarkably reduced the infarct size, and protected endothelial barrier integrity demonstrated by decreased endothelial cells apoptosis, microvascular permeability, and myocardial hemorrhage, fortified tight junction, and upregulated expression of JAM-A, integrin-α5, and VE-cadherin, and these effects of TXL were as effective as insulin and rhAngptl4. However, Angptl4 knock-down with siRNA interference and inhibition of PPAR-α with MK886 partially diminished these beneficial effects of TXL and rhAngptl4. TXL induced the expression of Angptl4 in I/R-injured diabetic hearts, and was canceled by Angptl4 siRNA and MK886. TXL treatment increased myocardial PPAR-α activity, and was abolished by MK886 but not by Angptl4 siRNA.
TXL protects diabetic hearts against I/R injury by activating Angptl4-mediated restoration of endothelial barrier integrity via the PPAR-α pathway.
探讨内皮屏障功能在心肌缺血/再灌注（I/R）损伤中的作用，以及通心络（TXL）在人心脏微血管内皮细胞缺氧/复氧过程中诱导血管生成素样 4（Angptl4）分泌的作用。本研究旨在探讨 TXL 是否能通过诱导 Angptl4 介导的内皮屏障完整性保护来减轻糖尿病心肌 I/R 损伤，其特征为微血管内皮屏障破坏。
通过在 ZDF 糖尿病和非糖尿病对照大鼠的冠状动脉结扎中创建 I/R 损伤。对动物进行麻醉，并随机分为假手术或 I/R 损伤，同时暴露于胰岛素、rhAngptl4、TXL、Angptl4 siRNA 和 PPAR-α 抑制剂 MK886。TXL、胰岛素和 rhAngptl4 对糖尿病心脏 I/R 损伤具有相似的保护作用。在 I/R 损伤的糖尿病心脏中，TXL 治疗显著减少梗死面积，并通过减少内皮细胞凋亡、微血管通透性和心肌出血来保护内皮屏障完整性，强化紧密连接，并上调 JAM-A、整合素-α5 和 VE-钙粘蛋白的表达，TXL 的这些作用与胰岛素和 rhAngptl4 一样有效。然而，用 siRNA 干扰敲低 Angptl4 和用 MK886 抑制 PPAR-α 部分减弱了 TXL 和 rhAngptl4 的这些有益作用。TXL 在 I/R 损伤的糖尿病心脏中诱导 Angptl4 的表达，并用 Angptl4 siRNA 和 MK886 消除。TXL 治疗增加了心肌 PPAR-α 活性，被 MK886 消除，但不受 Angptl4 siRNA 影响。
TXL 通过激活 Angptl4 介导的内皮屏障完整性恢复，通过 PPAR-α 途径保护糖尿病心脏免受 I/R 损伤。
