Abstract
ObjectiveEndothelial 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.Methods and resultsI/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.ConclusionsTXL protects diabetic hearts against I/R injury by activating Angptl4-mediated restoration of endothelial barrier integrity via the PPAR-α pathway.
Highlights
Reopening of the occluded coronary artery by mechanical or pharmacological intervention is critical for reduction of tissue injury in patients with acute myocardial infarction (AMI)
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
The mechanism of TXL against myocardial I/R injury involved the activation of protein kinase A (PKA)/endothelial nitric oxide synthase pathway, protection of microvascular endothelial integrity by up-regulating VE-cadherin, βcatenin, and γ-catenin, and subsequent reduction of myocardial hemorrhage, inflammation, oxidization, edema, apoptosis and necrosis, while eNOS inhibitor (Nω-Nitro-L-arginine) L-NNA completely canceled these effects of TXL, indicating that endothelial barrier function plays a key role in the development and TXL protection of myocardial I/R injury [3,4,5,6]
Summary
Reopening of the occluded coronary artery by mechanical or pharmacological intervention is critical for reduction of tissue injury in patients with acute myocardial infarction (AMI). It may trigger ischemia/reperfusion (I/R) injury, aggravating myocardial injury, decreasing and even counteracting the benefit of coronary blood flow restoration[1]. We found that TXL can directly reduce the apoptosis of cardiac microvascular endothelial cells by triggering autophagy [7] through modulating cytokines secretion [8], and angiopoietin-like protein 4 (Angptl4) was one of the dramatically up-regulated cytokines [8], indicating Angptl may be an important mediator in the cardioprotective effect of TXL against I/R injury
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