Abstract
Gossypetin (GTIN), known as 3,5,7,8,3′,4′-hexahydroxyflavone, has been demonstrated to exert anti-atherosclerotic potential against apoptotic injury in oxidized low-density lipoprotein-incubated endothelial cells, and atherosclerotic lesions of cholesterol-fed rabbits. However, the effect and underlying mechanism of GTIN on abnormal vascular smooth muscle cells (VSMCs) proliferation and migration, a major event in the pathogenesis of atherosclerosis, is still unknown. In this study, non-cytotoxic doses of GTIN abolished the VSMCs A7r5 proliferation and cell-cycle S phase distribution. The GTIN-arrested G0/G1 phase might be performed by increasing the expressions of phosphorylated p53 and its downstream molecules that inhibit the activation of cyclin E/cyclin-dependent kinase (cdk)-2, blocking retinoblastoma protein (Rb) phosphorylation and the subsequent dissociation of Rb/transcription factor E2F1 complex. In addition, the results indicated that GTIN inhibited VSMCs wound-healing and migratory abilities through reducing matrix metalloproteinase (MMP)-9 activity and expression, as well as down-regulating protein kinase B (PKB)/nuclear factor-kappaB (NF-κB) signaling. GTIN also revealed potential in diminishing reactive oxygen species (ROS) generation. These findings suggested the inhibitory effects of GTIN on VSMCs dysfunction could likely lead to the containment of atherosclerosis and other cardiovascular illness.
Highlights
A preliminary screening by MTT assay was carried out to evaluate the effect of GTIN at various concentrations on A7r5 viability for 24 h, and it was indicated that a range between 1 and 10 μM of GTIN was nontoxic for A7r5 cells, while GTIN at dose higher than 25 μM inhibited the cell viability (Figure 1a)
The result of cell growth curve declared that when GTIN at dosages above 1 μM
vascular smooth muscle cells (VSMCs) migration was majorly conducted via downGTIN against reactive oxygen species (ROS) generation may correct the degree of abnormal VSMCs proliferation and migration by down-regulating Akt/NF-κB signaling-mediated matrix metalloproteinase (MMP)-9 production and up-regulating p53 signaling-mediated retinoblastoma protein (Rb) phosphorylation that subsequently inhibited the development of atherosclerosis (Figure 6d)
Summary
Gossypetin (GTIN) is a natural hydroxylated flavone with extensive antioxidant, antimicrobial, anti-inflammation, and anti-tumor activities [1]. Previous studies have indicated that GTIN might be a multifunctional agent that performs its activities by diminishing. N-methyl-N0 -nitro-N0 -nitrosoguanidine (MNNG) mutagenicity [2], exerting antioxidant and anti-atherosclerotic effects [3,4], possessing anti-microbial property [5,6], and ameliorating gamma radiation-mediated DNA damage [7], as well as inducing apoptotic and autophagic cell death of cancer cells [8]. As regards the literature of anti-atherosclerosis, GTIN has been shown to be quite effective in the inhibition of low-density lipoprotein (LDL) modification, macrophage uptake, and subsequent foam cell formation, but in the promotion of cholesterol efflux [3]. A recent study noted that GTIN effectively suppressed atherosclerotic pathogenesis by exhibiting the protective effects against oxidized
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