Altered PDGF-BB–Induced p38 MAP Kinase Activation in Diabetic Vascular Smooth Muscle Cells

Abstract

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 ␤-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)-␤II and PKC-␦ were activated by diabetes, PDGF-BB could further enhance the level of PKC-␦ 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-␦. 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-␦ and the subsequent MKK 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetic VSMCs. Key Words: p38 Ⅲ PDGF-BB Ⅲ VSMC Ⅲ PKC Ⅲ migration D iabetes mellitus is a most crucial risk factor for atherosclerosis. 1,2 Several hypotheses, such as hyperosmolarity, 3 advanced glycation end products, 4 oxidant formation, 5 abnormality of sorbitol and myoinositol metabolism, 6 and diacylglycerol protein kinase C (PKC) activation, 7 have been proposed to explain the various pathological changes induced by hyperglycemia in vasculature. Glucose and its metabolites possibly mediate their adverse effects by altering the various signal transduction pathways used by vascular cells to perform their functions and maintain cellular integrity. Some changes in vascular cells include increases in contractility, cellular proliferation, migration, and extracellular matrix production, which are abnormal in diabetes. 7 We and other investigators recently identified that the activation of p38 mitogen-activated protein kinase (MAPK) could be responsible for some vascular dysfunctions observed in the diabetic state. 8 -11 However, it has not been determined whether hyperglycemia and its metabolites can affect other signal transduction systems and/or the cellular targets of p38 activation.In contrast, the platelet-derived growth factor (PDGF) is recognized as a major mitogen in serum and one of the most important growth factors that promote atherogenesis, including the proliferation of vascular smooth muscle cells (VSMCs). 12-15 PDGF-BB can bind all types of receptors and activate the GTPase-activating protein of Ras (Ras-GTP) and, subsequently, extracellular-regulated protein kinase (extracellular signal regulated kinase [ERK]) 1/2, leading to cellul...

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