Genipin Inhibits TNF-α-Induced Vascular Smooth Muscle Cell Proliferation and Migration via Induction of HO-1

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.

Protective effects of the polyphenols (+)-episesamin and sesamin against PDGF-BB-induced activation of vascular smooth muscle cells are mediated by induction of haem oxygenase-1 and inhibition of mitogenic signalling

“…These stimulatory effects of PDGF-BB were blocked by the presence of SE and ES. In addition, also the here shown ES/SE-mediated impaired HO-1 expression contributes to a reduced MMP secretion by VSMC, as also described earlier (Jiang et al, 2013).…”

“…Indeed, and confirming previous data (Jiang et al, 2013), the presence of ZnPP IX slightly enhanced the basal and also the PDGF-BB-induced gelatinolytic activity in VSMC supernatants (Fig. 4D).…”

“…This includes enhanced proliferation and migration of VSMC to the intima due to the exposure to proinflammatory cytokines and growth factors which are released by VSMC and macrophages (Hansson, 2005;Kher & Marsh, 2004;Swirski et al, 2009;Wen, Han, Zheng, & Yang, 2002). Besides tumour necrosis factor (TNF)-alpha Jiang, Jiang, Zhu, Zhang, & Zhan, 2013), PDGF-BB is a potent mitogenic or migratory stimulus for VSMCs and induces the generation of oxidative stress by reactive oxygen species (ROS) (Kim, Hwangbo, Lee, & Lee, 2013;Yamasaki et al, 2001;Yi et al, 2012). PDGF-BB also induces autophagy in VSMC which affects the transition from a contractile to a synthetic phenotype favouring VSMC survival under conditions of elevated ROS levels (Salabei et al, 2013), a characteristic feature during atherosclerosis (West, Guzik, Black, & Channon, 2001;Yokoyama, Inoue, & Kawashima, 2000).…”

Astragaloside IV inhibits platelet-derived growth factor-BB-stimulated proliferation and migration of vascular smooth muscle cells via the inhibition of p38 MAPK signaling

“…In addition, the p38 MAPK signaling pathway participates in the regulation of VSMC proliferation by modulating the expression of cell cycle-associated proteins (28). Furthermore, this signaling pathway is associated with VSMC migration (29).…”

IRE1α inhibition by natural compound genipin on tumour associated macrophages reduces growth of hepatocellular carcinoma

“…Genipin inhibited the NLRP3 and NLRC4 inflammasome resulted in attenuation of in vivo peritonitis and lung inflammation in mice [16]. The suppressive effect of genipin on vascular smooth muscle cell proliferation and migration also correlated to its anti-inflammatory function [17]. But how the anti-inflammatory property of genipin contributes to its anti-tumour effect and whether TAMs is involved remains unclear.…”