Abstract
Vascular smooth muscle cell (VSMC) proliferation and migration triggered by inflammatory stimuli contributes importantly to the pathogenesis of atherosclerosis and restenosis. On the other hand, genipin, an aglycon of geniposide, exhibits diverse pharmacological functions such as antitumor and anti-inflammatory effects. The protective effects of genipin on the cardiovascular system have also been reported. However, the molecular mechanism involved remains unknown. This study aimed to elucidate the precise function of genipin in VSMCs, focusing particularly on the role of heme oxygenase-1 (HO-1), a potent anti-inflammatory enzyme. We found that pretreatment of genipin induced HO-1 mRNA and protein levels, as well as its activity in VSMCs. Genipin inhibited TNF-α-induced VSMC proliferation and migration in a dose-dependent manner. At the molecular level, genipin prevented ERK/MAPK and Akt phosphorylation while left p38 MAPK and JNK unchanged. Genipin also blocked the increase of ROS generation induced by TNF-α. More importantly, the specific HO-1 siRNA partially abolished the beneficial effects of genipin on VSMCs. These results suggest that genipin may serve as a novel drug in the treatment of these pathologies by inducing HO-1 expression/activity and subsequently decreasing VSMC proliferation and migration.
Highlights
The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical events in the pathogenesis of atherosclerosis and restenosis [1]
To detect the effects of genipin on basal heme oxygenase-1 (HO-1) expression in VSMCs, 25 or 100 μM genipin was added to VSMCs, respectively
We showed that genipin inhibits TNF-αinduced VSMC proliferation and migration, activation of Erk/ MAPK and Akt pathways as well as ROS production
Summary
The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical events in the pathogenesis of atherosclerosis and restenosis [1]. Quiescent VSMCs stay in a “contractile” state when unchallenged, in response to various stimuli including inflammatory cytokine stimulation, VSMCs will switch to an active “synthetic” state, leading to uncontrolled proliferation and migration [3,4]. TNF-α regulates VSMC proliferation, migration and synthetic behavior [6] and induces the differentiation of VSMCs into osteoblast/chondrogenic cells, which causing calcium deposition and increasing arterial stiffness [7]. Inhibition of arterial inflammation and the subsequent VSMC proliferation and migration has high value in the treatment of atheroslcerosis and restenosis [8,9]
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