Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic Aldehyde Reduces Atherosclerosis and Attenuates Low-Shear Stress-Induced Vascular Endothelial Cell Dysfunction

Background: The Fufang Danshen formula is a clinically important anti-atherosclerotic preparation in traditional Chinese medicine. However, its anti-atherosclerotic effect is not well recognized, and the mechanisms of its combined active ingredients, namely Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic aldehyde (RRP), remain unclear. The purpose of this study was to investigate the anti-atherosclerotic effects and potential mechanism of RRP in ApoE−/− mice and in low-shear stress-injured vascular endothelial cells.Methods: ApoE−/− mice were randomly divided into three groups: model group, rosuvastatin group, and RRP group, with C57BL/6J mice as the control group. Oil-red O, hematoxylin and eosin, Masson, and Movat staining were utilized for the observation of aortic plaque. Changes in the blood lipid indexes were observed with an automatic biochemistry analyzer. ET-1, eNOS, TXA2, and PGI2 levels were analyzed by enzyme-linked immunosorbent assay. In vitro, a fluid shear stress system was used to induce cell injury. Piezo1 expression in HUVECs was silenced using siRNA. Changes in morphology, proliferation, migration, and tube formation activity of cells were observed after RRP treatment. Quantitative Real-Time PCR and western blot analysis were employed to monitor mRNA and protein expression.Results: RRP treatment reduced the atherosclerotic area and lipid levels and improved endothelial function in ApoE−/− mice. RRP significantly repaired cell morphology, reduced excessive cell proliferation, and ameliorated migration and tube formation activity. In addition, RRP affected the FAK-PI3K/Akt signaling pathway. Importantly, Piezo1 silencing abolished the protective effects of RRP.Conclusion: RRP has anti-atherosclerotic effects and antagonizes endothelial cell damage via modulating the FAK-PI3K/Akt signaling pathway. Piezo1 is a possible target of RRP in the treatment of atherosclerosis. Thus, RRP has promising therapeutic potential and broad application prospect for atherosclerosis.

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Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic aldehyde attenuates low shear stress-induced vascular endothelial cell dysfunction

10.21203/rs.3.rs-25782/v1 ◽

2020 ◽

Author(s):

Lei Zhang ◽

Yuan Li ◽

Xin Ma ◽

Xiaojie Wang ◽

Lingxiao Zhang ◽

...

Keyword(s):

Shear Stress ◽

Endothelial Cell ◽

Cell Injury ◽

Vascular Endothelial Cell ◽

Akt Signaling ◽

Tube Formation ◽

Vascular Endothelial ◽

Ginsenoside Rg1 ◽

Low Shear Stress ◽

Low Shear

Abstract Background The Fufang Danshen formula is widely used in traditional Chinese medicine for the clinical treatment of coronary heart disease. However, there is no literature reporting the anti-atherosclerotic effect and mechanism of its combination of active ingredients, namely Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic aldehyde (PPR). The aim of this study was to investigate the anti-atherosclerotic effects in ApoE−/− mice and potential mechanism of PPR in low shear stress-injured vascular endothelial cell. Methods In vivo assay, ApoE−/−mice were randomly divided into three groups: model group, Rosuvastatin group, and PPR group, with C57BL/6J mice as control group. A variety of staining methods were utilized for the observation of aortic plaque. The changes of the blood lipid indexes were observed by an automatic biochemistry analyzer. ET-1, eNOS, TAX2, and PGI2 were analyzed by enzymelinked immunosorbent assay. In vitro, we used fluid shear system to induce cell injury and silenced Piezo1 expression in HUVECs by siRNA. We observed the morphological, proliferation, migration and tube formation activity changes of cells after PPR intervention. Quantitative Real-Time PCR and western blot analysis was applied to observe m RNA and protein expression. Results Results showed that PPR treatment reduced atherosclerotic area and lipid level and improved endothelial function in ApoE−/− mice. PPR significantly repaired cell morphology, reduced cell excessive proliferation and ameliorated migration and tube formation activity. In addition, we found that PPR could affect FAK-PI3K/Akt signaling pathways. Importantly, Piezo1 siRNA abolished the protection effects of PPR. Conclusions In summary, our results suggested that PPR ameliorated atherosclerotic plaque formation and endothelial cell injury by intervening the FAK-PI3K/Akt signaling pathways. Piezo1 is a possible target of PPR in the treatment of atherosclerosis. These results indicate that PPR may be apotential drug for atherosclerosis.

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Knockdown of Nrf2 inhibits angiogenesis by downregulating VEGF expression through PI3K/Akt signaling pathway in cerebral microvascular endothelial cells under hypoxic conditions

Biochemistry and Cell Biology ◽

10.1139/bcb-2017-0291 ◽

2018 ◽

Vol 96 (4) ◽

pp. 475-482 ◽

Cited By ~ 17

Author(s):

Yujing Huang ◽

Ying Mao ◽

Huiying Li ◽

Guangxun Shen ◽

Guangxian Nan

Keyword(s):

Vascular Endothelial Growth Factor ◽

Ischemic Stroke ◽

Growth Factor ◽

Signaling Pathway ◽

Akt Signaling ◽

Tube Formation ◽

Vascular Endothelial ◽

Akt Signaling Pathway ◽

Microvascular Endothelial ◽

Endothelial Growth Factor

Ischemic stroke is a major cerebrovascular disease resulting from a transient or permanent local reduction of cerebral blood flow. Angiogenesis plays an important role in cerebral microvascular repair after ischemic stroke. This study aimed at investigating the effect of NF-E2-related factor 2 (Nrf2) on the angiogenesis of mouse cerebral microvascular endothelial bEnd.3 cells in a hypoxic environment. We found that Nrf2 expression was temporarily increased in hypoxia-induced bEnd.3 cells. Knockdown of Nrf2 inhibited the proliferation, migration, as well as tube formation in hypoxia-induced bEnd.3 cells. Meanwhile, vascular endothelial growth factor and PI3K/Akt signaling pathways were identified to be regulated by Nrf2 in hypoxia-induced bEnd.3 cells. It was found that silencing of Nrf2 downregulated the expression levels of NAD(P)H:quinine oxidoreductase-1, vascular endothelial growth factor, p-Akt, and heme oxygenase-1 in hypoxia-induced bEnd.3 cells. Data suggested that hypoxia induced the transient increase of Nrf2, which plays a key role in the angiogenesis of cerebral microangiogenesis, and that Nrf2 regulates the proliferation, migration, as well as tube formation likely through PI3K/Akt signaling pathway in hypoxia-induced bEnd.3 cells. Our study provides proof of concept for the modulation of Nrf2, so as to tilt the balance toward angiogenesis, representing a therapeutic strategy for hypoxia or ischemia disorders such as stroke.

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