The Src/PLC/PKC/MEK/ERK signaling pathway is involved in aortic smooth muscle cell proliferation induced by glycated LDL.
Low density lipoproteins (LDL) play important roles in the pathogenesis of atherosclerosis. Diabetes is associated with accelerated atherosclerosis leading to cardiovascular disease in diabetic patients. Although LDL stimulates the proliferation of arterial smooth muscle cells (SMC), the mechanisms are not fully understood. We examined the effects of native LDL and glycated LDL on the extracellular signal-regulated kinase (ERK) pathway. Addition of native and glycated LDL to rat aorta SMCs (RASMCs) stimulated ERK phosphorylation. ERK phosphorylation was not affected by exposure to the Ca2+ chelator BAPTA-AM but inhibition of protein kinase C (PKC) with GF109203X, inhibition of Src kinase with PP1 (5 microM) and inhibition of phospholipase C (PLC) with U73122/U73343 (5 microM) all reduced ERK phosphorylation in response to glycated LDL. In addition, pretreatment of the RASMCs with a cell-permeable mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059, 5 microM) markedly decreased ERK phosphorylation in response to native and glycated LDL. These findings indicate that ERK phosphorylation in response to glycated LDL involves the activation of PKC, PLC, and MEK, but is independent of intracellular Ca2+.
Cho
Hyun-Mi
HM
Department of Biochemistry, Kangwon National University, Chunchon 200-701, Korea.
Choi
Sung Hee
SH
Hwang
Ki-Chul
KC
Oh
Sue-Young
SY
Kim
Ho-Gyung
HG
Yoon
Deok-Hyo
DH
Choi
Myung-Ae
MA
Lim
Soyeon
S
Song
Heesang
H
Jang
Yangsoo
Y
Kim
Tae Woong
TW
D000818:Animals; D001011:Aorta / Q000166:cytology; D002460:Cell Line; D049109:Cell Proliferation; D005419:Flavonoids / Q000494:pharmacology; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093844:Glycated Proteins
D005419:Flavonoids; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; D020929:Mitogen-Activated Protein Kinase Kinases; D011493:Protein Kinase C; D011720:Pyrazoles; D011743:Pyrimidines; D010738:Type C Phospholipases; D019061:src-Family Kinases; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one