Macrophages Aggravate Hypoxia-Induced Cardiac Microvascular Endothelial Cell Injury via Peroxynitrite: Protection by Tongxinluo

Abstract

Activated macrophages contribute to endothelial dysfunction; however, it is unclear how peroxynitrite contributes to macrophage-mediated human cardiac microvascular endothelial cell (HCMEC) injury in hypoxia. In macrophage-HCMEC co-cultures subjected to hypoxia, there was an increase in hypoxia-inducible factor (HIF)-1a, HIF-2a, inducible nitric oxide synthase (iNOS), endothelin-converting enzyme (ECE)-1 and cyclooxygenase-2 (COX-2), and concomitant decrease in prostacyclin synthase (PGIS). This was mimicked by a peroxynitrite donor and attenuated by its decomposition catalyst. Tongxinluo (TXL) could decrease HIF-2a, iNOS, ECE-1 and COX-2 and increase PGIS in a dose-dependent manner, with increase of vascular endothelial growth factor. The protein alterations verified the remarkably affected mRNAs, indicating that the effects of TXL were similar to but better than that of peroxynitrite decomposition catalyst. Furthermore, TXL inhibited macrophage-mediated nitrotyrosine accumulation and attenuated HCMEC injury. The results suggest that peroxynitrite contributes to macrophage-mediated HCMEC injury in hypoxia, and TXL attenuates HCMEC injury mainly by inhibiting peroxynitrite. ARTICLE HISTORY

Inhibition of miR-128-3p by Tongxinluo Protects Human Cardiomyocytes from Ischemia/reperfusion Injury via Upregulation of p70s6k1/p-p70s6k1

“…TXL is a multifunctional traditional Chinese medicine reported to exert pleiotropic effects such as anti-fibrosis (Chen W. et al, 2008 ; Bai et al, 2013 ; Wang X. et al, 2016 ), anti-inflammation (Wang et al, 2015 ), anti-atherogenesis (Wu et al, 2015 ), anti-apoptosis (Cui et al, 2014 ; Wei et al, 2016 ) and improved microvascular barrier function (Liu et al, 2013 ; Li et al, 2015 ; Qi et al, 2015 ; Zheng et al, 2015 ). This multitude of activities can be explained by the variety of active ingredients in TXL (Cheng et al, 2009 ).…”

Qiliqiangxin attenuates hypoxia‐induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF‐1α‐dependent glycolysis

“…CMECs, a special cell type derived from coronary microvessels, play a major role in promoting angiogenesis and delivering oxygen to myocardium. The fact that HIF‐1α is elevated under hypoxic conditions has been confirmed in most types of endothelial cells, for example, human/rat cardiac microvascular endothelial cells and human umbilical vein endothelial cells (HUVECs) 28, 29, 30. As is known, activated HIF‐1α and its downstream effector VEGF are key regulators which can protect endothelial cells from hypoxia‐induced impairment and promote angiogenesis and cell migration 7.…”

“…The fact that HIF-1a is elevated under hypoxic conditions has been confirmed in most types of endothelial cells, for example, human/rat cardiac microvascular endothelial cells and human umbilical vein endothelial cells (HUVECs). [28][29][30] As is known, activated HIF-1a and its downstream effector VEGF are key regulators which can protect endothelial cells from hypoxia-induced impairment and promote angiogenesis and cell migration. 7 In the present study, however, with long-time hypoxia, the protective mechanism initiated by adaptive HIF-1a elevation seems decompensated and not sufficient.…”

Potential Effectiveness of Chinese Patent Medicine Tongxinluo Capsule for Secondary Prevention After Acute Myocardial Infarction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…Vascular injury after chronic hypoxia usually leads to endothelial injury and structural damage to tight junctions, TXL could promote endothelial cell proliferation and reverse the expression of tight junctions' proteins in vivo and in vitro (Zheng et al, 2015 ). Additionally, we found that TXL could regulate gene expression in hypoxia-treated human cardiac microvascular endothelial cells (CMECs) (Li Y. N. et al, 2015 ) and attenuate human CMEC injury via inhibiting peroxynitrite, which contributed to macrophage-mediated human CMEC injury (Wang et al, 2015 ).…”