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ABSTRACT: The purpose of this study was to determine the effect and associated cell signaling mechanisms of indole-3-carbinol (I3C) on platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of cultured vascular smooth muscle cells (VSMCs) and neointima formation in a carotid injury model. Our data demonstrated that I3C inhibited PDGF-BB-induced proliferation of VSMCs in a dose-dependent manner without causing cell cytotoxicity, as assessed by 5-bromo-2'-deoxyuridine incorporation and WST-1 assays. Further studies revealed that the antiproliferative effect of I3C was caused by the arrest of cells in both the G0/G1 and S phases. Moreover, I3C treatment inhibited migration of VSMCs and partly reversed the expression of smooth-muscle-specific contractile markers. We also demonstrated that I3C-induced growth inhibition was associated with an inhibition of the expression of cyclin D1 and cyclin-dependent kinase 4/6, as well as an increase in p27(Kip1) levels in PDGF-stimulated VSMCs. These beneficial effects of I3C on VSMCs appeared to be at least partly mediated by the inhibition of Akt and the subsequent activation of glycogen synthase kinase (GSK) 3β. Furthermore, using a mouse carotid artery injury model, we found that treatment with 150 mg/kg I3C resulted in a significant reduction of the neointima/media ratio and cells positive for proliferating cell nuclear antigen. These results demonstrate that I3C can suppress the proliferation and migration of VSMCs and neointima hyperplasia after vascular injury via inhibition of the Akt/GSK3β pathway and suggest that this might be feasible as part of a therapeutic strategy for vascular proliferative diseases.
The Journal of nutritional biochemistry 07/2012; · 4.29 Impact Factor
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ABSTRACT: Abnormal proliferation, migration, and phenotypic modulation of vascular smooth muscle cells (VSMCs) are critical factors in neointima formation during restenosis. The purpose of this study is to determine the efficacy and possible cell signaling mechanisms of apigenin in VSMC activation induced by platelet-derived growth factor (PDGF)-BB and injury-induced neointima formation. Our data revealed a dose-dependent apigenin inhibition of PDGF-BB-induced proliferation of VSMCs by arresting cells in G0/G1-phase of the cell cycle as determined using 5-bromo-2'-deoxyuridine incorporation and flow cytometry. This was associated with the inhibition of cyclin-dependent kinase (CDK) 4,6 expression and an increase in p27Kip1 levels in PDGF-stimulated VSMCs. Moreover, apigenin was also found to regulate PDGF-induced migration and expression of smooth-muscle-specific contractile markers. Mechanistically, the PDGF-BB-induced phosphorylation of PDGF-receptor β (PDGF-Rβ), Akt/glycogen synthase kinase(GSK)3β, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3) is negatively modulated by apigenin. For the in vivo studies using a mouse carotid arterial injury model, the administration of apigenin resulted in a significant inhibition of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells. These results demonstrate that apigenin can suppress PDGF-induced VSMC activation and neointima hyperplasia after vascular injury; these beneficial effects are probably the result of the blockade of PDGF-Rβ phosphorylation and its downstream signal transduction, including the Akt/GSK-3β, ERK1/2, and STAT3 pathways. The results suggest that apigenin may be a potential therapeutic candidate for the prevention of restenosis.
Journal of Cellular Biochemistry 11/2011; 113(4):1198-207. · 2.87 Impact Factor
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Chunming Shu, Changgui Chen,
Da-Ping Zhang,
Haipeng Guo,
Heng Zhou,
Jing Zong,
Zhouyan Bian,
Xuan Dong,
Jia Dai,
Yan Zhang,
Qizhu Tang
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ABSTRACT: Phenolic glucoside gastrodin (Gas), which is a main component extracted from the Chinese herbs Gastrodia elata Bl, is a well-known natural calcium antagonist with antioxidant and anti-inflammatory functions. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. Previous studies have shown that gastrodin possesses comprehensive pharmacological functions. However, very little is known about whether gastrodin has protective role on cardiac hypertrophy. The aim of this study was to determine whether gastrodin attenuates pressure overload-induced cardiac hypertrophy in mice and to clarify the underlying molecular mechanisms. Our data demonstrated that gastrodin prevented cardiac hypertrophy induced by aortic banding (AB), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardiographic parameters, and gene expression of hypertrophic markers. The inhibitory effect of gastrodin on cardiac hypertrophy is mediated by ERK1/2 signaling and GATA-4 activation. Further studies showed that gastrodin attenuated fibrosis and collagen synthesis through abrogating ERK1/2 signaling pathway. Therefore, these findings indicated that gastrodin, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis through suppression of ERK1/2 signaling.
Molecular and Cellular Biochemistry 07/2011; 359(1-2):9-16. · 2.06 Impact Factor
