Regulation of Src homology 2-containing protein tyrosine phosphatase by advanced glycation end products: the role on atherosclerosis in diabetes.
Advanced glycation end products (AGEs), among the most important causes of atherosclerosis in diabetes mellitus, stimulate the proliferation of smooth muscle cells (SMCs). Smooth muscle cells are central in the formation of atherosclerotic lesions, where they show both increased migration and accelerated proliferation. In investigating how AGEs stimulate SMC proliferation, we focused on protein tyrosine phosphatase, especially Src homology 2-containing protein tyrosine phosphatase (SHP2), which is considered important in regulating cell proliferation. Advanced glycation end products increased activity of SHP2 in the membrane fraction of rat aortic SMCs compared with control bovine serum albumin (P < .05). Upon characterizing the genomic and promoter structure of SHP2, we detected nuclear factor-kappaB (NF-kappaB) binding sites in the promoter area. Advanced glycation end product stimulation increased luciferase activity in cells transfected with SHP2 promoter region including NF-kappaB binding sites (P < .05) and increased SHP2 expression (P < .05). These data indicate that AGE stimulation appears to activate NF-kappaB. Activated NF-kappaB binds to sites on the SHP2 promoter, resulting in increased SHP2 expression, SHP2 activity, and, ultimately, SMC proliferation. It suggests that AGE stimulation induces SMC proliferation via SHP2, underscoring the importance of control of AGE for suppressing macroangiopathy in diabetes mellitus.
Seki
Naoto
N
Clinical Research Center, National Hospital Organization, Chiba-East National Hospital, Chiba 260-8712, Japan.
Hashimoto
Naotake
N
Taira
Masato
M
Yagi
Sayaka
S
Yoshida
Yuriko
Y
Ishikawa
Kou
K
Suzuki
Yoshifumi
Y
Sano
Hiroyuki
H
Horiuchi
Seikou
S
Yoshida
Shouji
S
Sakurai
Kenichi
K
Yagui
Kazuo
K
Makino
Hideichi
H
Saito
Yasushi
Y
D000818:Animals; D001011:Aorta / Q000201:enzymology; D050197:Atherosclerosis / Q000503:physiopathology*; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000503:physiopathology*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D051381:Rats
D017931:DNA Primers; D017127:Glycation End Products, Advanced; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11