Activation of PKCbeta(II) and PKCtheta is essential for LDL-induced cell proliferation of human aortic smooth muscle cells via Gi-mediated Erk1/2 activation and Egr-1 upregulation.
Native LDL may be a mitogenic stimulus of VSMC proliferation in lesions where endothelial disruption occurs. Recent studies have demonstrated that the mitogenic effects of LDL are accompanied by Erk1/2 activation via an unknown G-protein-coupled receptor (GPCR). In this article, we report that LDL translocated PKCbeta(II) and PKCtheta from cytosol to plasma membrane, and inhibition of PKCbeta(II) and PKCtheta decreased LDL effects via the deactivation of Erk1/2. Moreover, pertussis toxin, but not cholera toxin or heparin, inhibited LDL-induced translocation of PKCbeta(II) and PKCtheta, suggesting that Gi protein plays a role in LDL effects. Of LPA, S1P, and LDL, whose signaling is conveyed via Gi/o proteins, only LDL induced translocation of PKCbeta(II) and PKCtheta. Inhibition of PKCbeta(II) or PKCtheta, as well as of Erk1/2 and GPCR, decreases LDL-induced upregulation of Egr-1, which is critical for cell proliferation. This is the first report, to our knowledge, that the participation of PKCtheta in VSMC proliferation is unique.
Heo
Kyung-Sun
KS
Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong, Daejeon, Republic of Korea.
Kim
Dong-Uk
DU
Kim
Lila
L
Nam
Miyoung
M
Baek
Seung-Tae
ST
Park
Song-Kyu
SK
Park
Youngwoo
Y
Myung
Chang-Seon
CS
Hwang
Sung-Ook
SO
Hoe
Kwang-Lae
KL
D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D008078:Cholesterol, LDL / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D000074121:Protein Kinase C-theta; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D008078:Cholesterol, LDL; D051766:Early Growth Response Protein 1; D007527:Isoenzymes; D043562:Receptors, G-Protein-Coupled; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000074121:Protein Kinase C-theta; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go