Abstract
The initiation of atherosclerosis (AS) induced by dyslipidemia is accompanied by endothelial dysfunction, including decreased healing ability and increased recruitment of monocytes. Studies showed ginsenoside Rg3 has potential to treat diseases associated with endothelial dysfunction which can protects against antineoplastic drugs induced cardiotoxicity by repairing endothelial function, while the effect and mechanism of Rg3 on dyslipidemia induced endothelial dysfunction and AS are not clear. Therefore, we investigated the effects of Rg3 on oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) dysfunction and high-fat diets (HFD) induced atherosclerosis in ApoE−/− mice, as well as the mechanism. For in vitro assay, Rg3 enhanced healing of HUVECs and inhibited human monocytes (THP-1) adhesion to HUVECs disturbed by ox-LDL, down-regulated focal adhesion kinase (FAK)-mediated expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1); restrained the FAK-mediated non-adherent dependent pathway containing matrix metalloproteinase (MMP)-2/9 expression, activation of nuclear factor-kappa B (NF-κB), high mRNA levels of monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6), besides Rg3 up-regulated peroxisome proliferators-activated receptor γ (PPARγ) in ox-LDL-stimulated HUVECs. GW9662, the PPARγ-specific inhibitor, can repressed the effects of Rg3 on ox-LDL-stimulated HUVECs. For in vivo assay, Rg3 significantly reduced atherosclerotic pathological changes in ApoE−/− mice fed with HFD, up-regulated PPARγ, and inhibited activation FAK in aorta, thus inhibited expression of VCAM-1, ICAM-1 in intima. We conclude that Rg3 may protect endothelial cells and inhibit atherosclerosis by up-regulating PPARγ via repressing FAK-mediated pathways, indicating that Rg3 have good potential in preventing dyslipidemia induced atherosclerosis.
Highlights
Atherosclerosis (AS) is a chronic, low-grade inflammationrelated disease
To determine whether Rg3 protects endothelial function stimulated by oxidized low-density lipoprotein (ox-low-density lipoprotein (LDL)), we first investigated the effects of Rg3 on endothelial cell healing, as shown in Figure 1C, oxLDL inhibited endothelial cell healing after scratching, whereas 30 mM Rg3 significantly reversed human umbilical vein endothelial cells (HUVECs) healing repressed by ox-LDL
Dyslipidemia cover a wide range of lipoprotein abnormalities, including elevated levels of low-density lipoprotein cholesterol, total cholesterol, and total triglyceride, as well as decreased levels of high density lipoprotein cholesterol, especially the LDL receptors were firmly up-regulated in cholesterol metabolism (Goldstein and Brown, 2015), LDL can be ingested and modificated into ox-LDL exhibit a variety of proatherogenic properties on vascular cultured cells (Salvayre et al, 2016), and the intervention of ox-LDL for vascular cells in study of AS in vitro has been widely used
Summary
Atherosclerosis (AS) is a chronic, low-grade inflammationrelated disease. Dyslipidemia is one of the most common and important factors leading to atherosclerosis (Fava and Montagnana, 2018), notably, low-density lipoprotein (LDL) is a main contributor to AS, superabundant LDL can be oxidized into ox-LDL, which primary damages the endothelial barrier, interferes with endothelial healing function emerges the subendothelial space (Goyal et al, 2012). Initiation of early AS induced by ox-LDL accompanied with recruiting monocytes by endothelial cells derived ligands, mainly including vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), the monocytes enter into the subendothelial space and transform into foam cells, developing into atherosclerotic plaques (Takami et al, 1998; Tsai et al, 2016), it is important to protect function of endothelial cells against interference of exogenous factors in anti-atherosclerosis (Wu et al, 2017; Zhi et al, 2019). Chen et al showed that the FAK-mediated nuclear factor kappa B (NFkB) signaling pathway was involved in Ang II-accelerated atherosclerosis, characterized by the atherosclerotic lesion macrophage content and plaque instability increased (Chen et al, 2018), indicating that FAK may active non-adhesion dependent signals to accelerate AS
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