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

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.

Uncovering the protective mechanism of Taohong Siwu decoction against diabetic retinopathy via HIF-1 signaling pathway based on network analysis and experimental validation

“…6 b) could regulate the expression of VEGF. For example, some researchers proved that baicalin [ 33 , 34 ], paeoniflorin [ 35 – 38 ] and stigmasterol [ 39 ] reduced the expression of VEGF and had a powerful effect on anti-angiogenesis, which were consistent with our findings.…”

Combined Therapy with Traditional Chinese Medicine and Antiplatelet Drugs for Ischemic Heart Disease: Mechanism, Efficacy, and Safety

“…Studies have shown that Panax notoginseng saponins reduce advanced glycosylation end product-induced apoptosis of human umbilical vein endothelial cells (HUVECs) by upregulating silent mating type information regulation 2 homolog 1 (SIRT1) [ 18 ]; these saponins also protect the microvessels of the brain by activating the phosphoinositide 3-kinase (PI3K)/Akt/nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathways [ 19 ]. Studies on paeoniflorin have also confirmed its vasoprotective effects [ 20 , 21 ]. Ligustrazine has an inhibitory effect on platelet adhesion, and its mechanism involves the inhibition of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF- κ B) signaling pathways to downregulate endothelial inflammation [ 22 ].…”

Treatment of tibial dyschondroplasia with traditional Chinese medicines: “Lesson and future directions”

“… Name Active components Biological activity Mechanism of action References Morinda officinalis Iridoids glycoside Antiapoptotic and anticatabolic, anti-inflammatory ↓ Proinflammatory cytokines ↓ MMP-3 and MMP-13 ( Wang et al., 2014 ) Resveratrol Phytoalexin, polyphenolic Regulates apoptosis, degrades extracellular matrix and protects chondrogenesis ↑ Sirt1 ↓ MMP1, MMP3 and MMP13, NF-κB and p38MAPK pathways. ( Liu et al., 2017b ; Jin et al., 2018 ; Wang and Bai, 2019 ) Rhizoma atractylodis macrocephalae Sesquiterpene, atractylenolide Promotes chondrogenic differentiation ↓Osteoclast differentiation ( Li et al., 2012 ) Fructus psoraleae Volatile oil, coumarin, flavones, lipids, resins Promotes viability and cartilaginous formation ↑ Type II collagen ↑ Aggrecan, and Sox-9 ( Pan et al., 2016 ) Semen plantaginis Flavonoids, triterpenoids, iridoid glycosides Antioxidant ↓VEGF, HIF-1α ( Tzeng et al., 2016 ) Hesperetin Flavonoids Antioxidant and antiapoptotic TLR4/NF-κB, Nrf2 pathways ( Chen et al., 2019 ; Muhammad et al., 2019 ) Paeoniflorin Paeoniflorin Angiogenesis ↓VEGF/VEGFR2 ↓Jagged1/Notch1 ( Yuan et al., 2018 ) Daidzein Flavonoids, isoflavones Antioxidant ( Yi et al., 2019 ) Curculigo orchioides Phenols and phenolic glycosides Antioxidant ↑Caspase-3 and caspase-8, ROS-mediated, ↓Bcl-2 ( Hejazi et al., 2018 ) Paeonol Paeonol Antiapoptotic a...…”