Effect of sinomenine on vascular smooth muscle cell dedifferentiation and neointima formation after vascular injury in mice.
Sinomenine, a pure alkaloid extract from Sinomenium acutum, has anti-inflammatory and immunoregulatory functions. This study investigated the efficiency and the signalling pathways involved in the effect of sinomenine on vascular smooth muscle cell (VSMC) dedifferentiation in response to platelet-derived growth factor (PDGF)-BB stimulation and vascular injury. VSMCs were isolated from rat aorta and preincubated with sinomenine before being stimulated with PDGF-BB. WST and BrdU incorporation assays were used to evaluate VSMC proliferation. Flow cytometric analysis was performed for testing the cell cycle progression. The cell migration of VSMCs were analysed using a Transwell system. The expression of VSMC specific genes and signalling proteins were tested by Western blot. For the animal study, C57/BL6 mice were fed either normal rodent chow diets or sinomenine chow diets that supplemented with 0.09 % sinomenine (w/w) in the normal chows for 14 days before carotid artery wire injury. PDGF-BB activated the dedifferentiation of VSMCs characterised by decreased expression of SMA, Smoothelin and SM22α. However, sinomenine treatment preserved the dedifferentiation in response to PDGF-BB. The activations of mitogen-activated protein kinase extracellular signal-regulated kinases, Akt, GSK3β and STAT3 induced by PDGF-BB were also inhibited in sinomenine-treated VSMCs. In vivo evidence with wire-injured mice exhibited a reduction in neointimal area and an increase in smooth muscle-specific gene expression in the sinomenine-treated group. In this study, we found that sinomenine-suppressed VSMC phenotype switching induced by PDGF-BB in vitro and neointimal formation in vivo. Therefore, sinomenine is a potential candidate to be used in the treatment of vascular proliferative disease.
Department of Cardiology, Renmin Hospital of Wuhan University, JieFang Road 238, Wuhan 430060, People's Republic of China.
Lihua
L
Zhu
Yarong
Y
Hao
Hongjing
H
Guan
Changping
C
Cui
Song
S
Tian
Da
D
Yang
Xinan
X
Wang
Shuming
S
Zhang
Lang
L
Wang
Hong
H
Jiang
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D054337:Cell Dedifferentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009019:Morphinans / Q000494:pharmacology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D058426:Neointima / Q000517:prevention & control*; D010641:Phenotype; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
D009019:Morphinans; D009124:Muscle Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C009271:sinomenine; D017479:Receptors, Platelet-Derived Growth Factor