Tetramethylpyrazine and Paeoniflorin Inhibit Oxidized LDL-Induced Angiogenesis in Human Umbilical Vein Endothelial Cells via VEGF and Notch Pathways.

Rong Yuan,Maggie Puiman Hoi,Weili Shi,Keji Chen,Binrui Yang,Qiqi Xin,Simon Mingyuan Lee,Weihong Cong

doi:10.1155/2018/3082507

Abstract

Atherosclerotic plaque angiogenesis is key factor in plaque instability and vulnerability, and low concentrations of oxidized low density lipoprotein (ox-LDL) promote the in vitro angiogenesis of endothelial cells and play an important role in plaque angiogenesis. Ligusticum chuanxiong Hort. and Radix Paeoniae Rubra herb pair in Chinese medicine obtains the optimum therapeutic efficacy in atherosclerosis, and their major active ingredients tetramethylpyrazine (TMP) and paeoniflorin (PF) are reported to alleviate atherosclerosis. The aim of this study was to investigate the effects of TMP and PF on ox-LDL-induced angiogenesis and the underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were incubated with ox-LDL and were then treated with TMP, PF, or a combination of TMP and PF. Cell proliferation, migration, tube formation, and the expression of angiogenesis-related proteins were measured. Synergism was evaluated using the combination index in cell proliferation. We found that TMP and PF attenuated the in vitro angiogenesis in ox-LDL-induced HUVECs. In addition, the combination of TMP and PF not only inhibited the ox-LDL-induced expression of CD31, vascular endothelial growth factor (VEGF), and VEGF receptor 2 (VEGFR2) but also decreased the ox-LDL-induced expression of Notch1, Jagged1, and Hes1. In summary, the combination of TMP and PF suppresses ox-LDL-induced angiogenesis in HUVECs by inhibiting both the VEGF/VEGFR2 and the Jagged1/Notch1 signaling pathways, which might contribute to the stability of plaques in atherosclerosis.

Highlights

Acute coronary syndrome is often related to atherosclerotic plaque rupture and thrombosis, while angiogenesis is a key factor in plaque destabilization leading to rupture [1, 2]
20 ug/ml oxidized low density lipoprotein (ox-LDL) enhanced Human umbilical vein endothelial cells (HUVECs) proliferation at 24 h when compared with control group (P
Our findings revealed that the combination of TMP and PF exhibited an antiangiogenic effect on ox-LDL-induced HUVECs, and the inhibitory effect was associated with its suppression of the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) and the Jagged1/Notch1 signaling pathways

Summary

Introduction

Acute coronary syndrome is often related to atherosclerotic plaque rupture and thrombosis, while angiogenesis is a key factor in plaque destabilization leading to rupture [1, 2]. Angiogenesis is a complex process that involves cell proliferation, migration, basement membrane degradation, and neovessel organization and maturation. Several studies suggest that angiogenesis contributes to the growth of atherosclerotic lesions and plaque destabilization by aggravating inflammation-related injury and causing intraplaque hemorrhage [3,4,5]. Oxidized low density lipoprotein (oxLDL) is, at least in part, responsible for angiogenesis in atherosclerotic regions [6]. Previous studies have demonstrated that low concentrations of ox-LDL promote angiogenesis in human endothelial cells, leading to plaque vulnerability and intravascular thrombosis [7,8,9,10]. The inhibition of angiogenesis has been considered as a potential therapeutic target in atherosclerosis [11]

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