Puerarin attenuates high-glucose-and diabetes-induced vascular smooth muscle cell proliferation by blocking PKCbeta2/Rac1-dependent signaling.
Oxidative stress has been implicated in several steps leading to the development of diabetic vascular complications. The purpose of this study was to determine the efficacy and the possible mechanism of puerarin on high-glucose (HG; 25 mM)-induced proliferation of cultured rat vascular smooth muscle cells (VSMCs) and neointimal formation in a carotid arterial balloon injury model of obese Zucker rats. Our data demonstrated that puerarin significantly inhibited rat VSMC proliferation as well as reactive oxygen species (ROS) generation and NADPH oxidase activity induced by HG treatment. Further studies revealed that HG treatment resulted in phosphorylation and membrane translocation of PKCbeta2 as well as Rac1, p47phox, and p67phox subunits, leading to NADPH oxidase activation. Puerarin treatment remarkably disrupted the phosphorylation and membrane translocation of PKCbeta2 as well as Rac1, p47phox, and p67phox subunits. Blocking PKCbeta2 by infection with AdDNPKCbeta2 also abolished HG-induced phosphorylation and membrane translocation of Rac1, p47phox, and p67phox subunits as well as ROS production and NADPH oxidase activation in VSMCs. In vivo neointimal formation of obese Zucker rats evoked by balloon injury was evidently attenuated by the administration of puerarin. These results demonstrate that puerarin may exert inhibitory effects on HG-induced VSMC proliferation via interfering with PKCbeta2/Rac1-dependent ROS pathways, thus resulting in the attenuation of neointimal formation in the context of hyperglycemia in diabetes mellitus.
Zhu
Li-Hua
LH
Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430060, PR China.
Wang
Lang
L
Wang
Dong
D
Jiang
Hong
H
Tang
Qi-Zhu
QZ
Yan
Ling
L
Bian
Zhou-Yan
ZY
Wang
Xin-An
XA
Li
Hongliang
H
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D003920:Diabetes Mellitus / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007529:Isoflavones / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D018384:Oxidative Stress; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D007529:Isoflavones; D017382:Reactive Oxygen Species; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D020830:rac1 GTP-Binding Protein; D005947:Glucose; C033607:puerarin