Tyrosine kinase-mediated activation of NADPH oxidase enhances proliferative capacity of diabetic vascular smooth muscle cells.
To investigate a potential molecular basis for a link between diabetes and atherosclerosis, experiments were performed to determine the role of NADPH oxidase in the enhanced proliferative capacity of vascular smooth muscle cells (VSMC) from OLETF rat, an animal model of type 2 diabetes. An enhanced proliferative response to 10% fetal bovine serum with an increased cell cycle progression from G1 to S phase as well as an augmented superoxide generation with an increased NADPH oxidase activity were observed in diabetic versus control VSMC. Both the enhanced proliferation and superoxide generation in diabetic VSMC were significantly attenuated not only by diphenyleneiodonium (10 microM) and apocynin (100 microM), NADPH oxidase inhibitors but also by protein tyrosine kinase inhibitors such as genistein (100 microM) and AG 112 (100 microM). Furthermore, the enhanced NADPH oxidase activity in diabetic VSMC was significantly attenuated by genistein and AG112, but not by daidzein (100 microM), a genistein analogue devoid of protein tyrosine kinase inhibitory properties. Based on these results, it is suggested that the enhanced proliferative capacity of diabetic VSMC is closely related to the activation of NADPH oxidase that is induced through activation of protein tyrosine kinase.
Jeong
Hye Young
HY
Department of Pharmacology and Internal Medicine, College of Medicine, Research Institute of Genetic Engineering and Medical Research Institute, Pusan National University, 10 Ami-Dong 1-Ga, Seo-Gu, Busan 602-739, South Korea.
Son
Seok Man
SM
Kim
Yong Ki
YK
Yun
Mi Ran
MR
Lee
Sun Mi
SM
Kim
Chi Dae
CD
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D013481:Superoxides / Q000378:metabolism
D013481:Superoxides; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases