Inhibition of neointimal hyperplasia in the rat carotid artery injury model by a HMGB1 inhibitor.

High mobility group box 1 protein (HMGB1) is expressed in atherosclerotic lesions. However, its role in vascular system is unknown. In this study, we explore whether the inhibition of HMGB1 attenuates neointimal formation in animal models. Experiments were performed with VSMCs from thoracic aorta of SD rats in vitro, and a rat carotid artery balloon injury model in vivo. HMGB1 levels were increased after stimulation of angiotensin II (Ang II) and 10% serum in cultured VSMCs. HMGB1 inhibitor (glycyrrhizin) significantly inhibited the proliferation and migration of Ang II-treated VSMCs, which was accompanied with decreased oxidative stress and inflammation. The underlying mechanisms were related with the promotion of antioxidant systems activity and deactivation of p38 MAPK/NF-κB signaling pathway, respectively. Furthermore, inhibition of HMGB1 blunted Notch signaling pathway during VSMCs phenotypic transition, and correspondingly restored VSMCs differentiated phenotype under 10% serum stimulation. In vivo study, HMGB1 expression was elevated after artery injury. Meanwhile, glycyrrhizin treatment suppressed HMGB1 expression, which was accompanied with blunted inflammation and oxidative stress after 7 days of balloon injury. Moreover, the area of neointimal to media area ratio was significantly decreased in glycyrrhizin group compared with injury group at 14 days after balloon injury. Inhibition of HMGB1 activity attenuated VSMCs activation and neointimal formation after carotid injury. Therefore, blockage of HMGB1 might represent a novel therapeutic strategy for vascular injury.

Chen J ，Zhang J ，Xu L ，Xu C ，Chen S ，Yang J ，Jiang H ... -  《-》

Naringenin inhibits angiotensin II-induced vascular smooth muscle cells proliferation and migration and decreases neointimal hyperplasia in balloon injured rat carotid arteries through suppressing oxidative stress.

Xu C ，Chen J ，Zhang J ，Hu X ，Zhou X ，Lu Z ，Jiang H ... -  《-》

Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-α/NF-κB pathway.

Reactive oxygen species (ROS) play a pivotal role in neointima hyperplasia after balloon injury. Molecular hydrogen has emerged as a novel antioxidant and has been proven effective in treating many diseases. We aimed to determine the mechanism by which hydrogen affects neointima formation. We assessed the influence of a hydrogen-rich saline solution (HRSS) by daily injection in rats. Rats were euthanized to evaluate the neointima. ROS, malondialdehyde (MDA) and superoxide dismutase (SOD) and reduced glutathione (GSH), were detected in the injured artery. Macrophage infiltration and the production of inflammatory factors (i.e., IL-6, TNF-α and NF-κB) were also observed. The in vitro effects of hydrogen on vascular smooth muscle cell (VSMC) proliferation were also measured. HRSS decreased the neointima area significantly. The neointima/media ratio was also reduced by HRSS. There was a decline in the number of PCNA-positive cells in the intima treated with HRSS. Meanwhile, HRSS ameliorated the ROS and MDA levels and increased SOD, reduced GSH levels in the injured carotid. In addition, the levels of inflammatory factors, such as IL-6, TNF-α and NF-κB p65, were attenuated by HRSS. In vitro studies also confirmed the anti-proliferative capability of the hydrogen solution and ROS generation in VSMCs induced by PDGF-BB. HRSS may have a protective role in the prevention of neointima hyperplasia and restenosis after angioplasty. HRSS may partially exert its role by neutralizing the local ROS and suppressing the TNF-α/NF-κB pathway.

Qin ZX ，Yu P ，Qian DH ，Song MB ，Tan H ，Yu Y ，Li W ，Wang H ，Liu J ，Wang Q ，Sun XJ ，Jiang H ，Zhu JK ，Lu W ，Huang L ... -  《-》

Resveratrol inhibits phenotypic switching of neointimal vascular smooth muscle cells after balloon injury through blockade of Notch pathway.

Zhang J ，Chen J ，Xu C ，Yang J ，Guo Q ，Hu Q ，Jiang H ... -  《-》

Resveratrol attenuates oxidative stress induced by balloon injury in the rat carotid artery through actions on the ERK1/2 and NF-kappa B pathway.

Oxidative stress plays a critical role in pathogenesis of the neointimal arterial hyperplasia. The aim of the study was to evaluate effects of resveratrol (RSV) on the vascular hyperplasia stimulated by oxidative damage. Balloon vascular injury was induced in rats that were intraperitonealy exposed to resveratrol (1 mg/kg) on 7 or 14 days after surgical procedure. Animals were euthanized on 7 or 14 days after operation. The blood level of 8-iso-prostaglandin F2α, arterial morphology as well as expression of monocyte chemotactic protein-1 and interleukin-6 in carotid wall were measured. Vascular smooth muscle cells (VSMCs) were isolated from the thoracic aorta. Cellular proliferation and migration assays, reactive oxygen species (ROS), superoxide dismutase (SOD) and NADPH oxidative activity, protein level of β-actin, histone H3, NF-ĸB p65, IĸB, ERK1/2, phospho-ERK1/2, phospho-p38 as well as NF-ĸB transcription activity were evaluated in-vitro after angiotensin II stimulation and resveratrol (50-200 µmol/L) treatment. Significant decreases in neointimal/medial area, serum prostaglandin level and genes expression were found in rats treated with resveratrol, when compared to the control group. Significant changes were also revealed for proliferation and migration rates, ROS level, as well as SOD, NADPH oxidase, ERK1/2 phosphorylation and NF-ĸB transcriptional activity in cell cultures exposed to highest dose of resveratrol. Insignificant changes were observed for NF-kappaB p65 translocation and IĸB degradation, p38 phosphorylation in MAPK pathway. Resveratrol significantly suppressed the neointimal hyperplasia after balloon injury through inhibition of oxidative stress and inflammation by blocking the ERK1/2/NF-kappa B pathway.

Zhang J ，Chen J ，Yang J ，Xu CW ，Pu P ，Ding JW ，Jiang H ... -  《-》