Altered PDGF-BB-induced p38 MAP kinase activation in diabetic vascular smooth muscle cells: roles of protein kinase C-delta.
OBJECTIVE
We investigated the regulation of p38 mitogen-activated protein kinase (MAPK) by platelet-derived growth factor (PDGF)-BB and its biological effects in cultured normal and diabetic rat vascular smooth muscle cells (VSMCs).


RESULTS
VSMC growth from diabetic rats was faster than that from normal rats. The expression of the PDGF beta-receptor in diabetic VSMCs was significantly elevated compared with that in normal cells, and PDGF-BB-induced p38 phosphorylation in diabetic cells was more enhanced via MAPK kinase (MKK) 3/6. The level of PKC activity in diabetic cells increased more than that in normal cells with or without PDGF-BB. Although protein kinase C (PKC)-betaII and PKC-delta were activated by diabetes, PDGF-BB could further enhance the level of PKC-delta alone. PDGF-BB-induced cell migration was more elevated in diabetic VSMCs, and the increase was significantly inhibited by SB-203580, rottlerin, and antisense oligodeoxynucleotides for PKC-delta. PDGF-BB-induced p38 phosphorylation also regulated cell growth, cyclooxygenase-2 levels, and arachidonic acid release, but not apoptosis. These levels were more elevated in diabetic cells, which were inhibited by SB-203580.


CONCLUSIONS
Our study established that PDGF-BB phosphorylated p38 via PKC-delta and the subsequent MKK 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetic VSMCs.
Yamaguchi
Hiroshi
H
Third Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
Igarashi
Masahiko
M
Hirata
Akihiko
A
Sugae
Naoko
N
Tsuchiya
Hiromi
H
Jimbu
Yumi
Y
Tominaga
Makoto
M
Kato
Takeo
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016718:Arachidonic Acid / Q000378:metabolism; D000077214:Becaplermin; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D051546:Cyclooxygenase 2; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D051745:Protein Kinase C-delta; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D007527:Isoenzymes; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases