Altered PDGF-BB–Induced p38 MAP Kinase Activation in Diabetic Vascular Smooth Muscle Cells: Roles of Protein Kinase C-δ

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). Methods and Results— VSMC growth from diabetic rats was faster than that from normal rats. The expression of the PDGF β-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)-βII and PKC-δ were activated by diabetes, PDGF-BB could further enhance the level of PKC-δ 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-δ. 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-δ and the subsequent MKK 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetic VSMCs.