Journal of Applied Physiology
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J Appl Physiol 91: 1412-1420, 2001;
8750-7587/01 $5.00
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Vol. 91, Issue 3, 1412-1420, September 2001

Activation of MAPK by modified low-density lipoproteins in vascular smooth muscle cells

Victoria Velarde*, Alicia J. Jenkins*, Julie Christopher, Timothy J. Lyons, and Ayad A. Jaffa

Departments of Medicine and Pharmacology, Division of Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, Charleston, South Carolina 29425

A high concentration of circulating low-density lipoproteins (LDL) is a major risk factor for atherosclerosis. Native LDL and LDL modified by glycation and/or oxidation are increased in diabetic individuals. LDL directly stimulate vascular smooth muscle cell (VSMC) proliferation; however, the mechanisms remain undefined. The extracellular signal-regulated kinase (ERK) pathway mediates changes in cell function and growth. Therefore, we examined the cellular effects of native and modified LDL on ERK phosphorylation in VSMC. Addition of native, mildly modified (oxidized, glycated, glycoxidized) and highly modified (highly oxidized, highly glycoxidized) LDL at 25 µg/ml to rat VSMC for 5 min induced a fivefold increase in ERK phosphorylation. To elucidate the signal transduction pathway by which LDL phosphorylate ERK, we examined the roles of the Ca2+/calmodulin pathway, protein kinase C (PKC), src kinase, and mitogen-activated protein kinase kinase (MEK). Treatment of VSMC with the intracellular Ca2+ chelator EGTA-AM (50 µmol/l) significantly increased ERK phosphorylation induced by native and mildly modified LDL, whereas chelation of extracellular Ca2+ by EGTA (3 mmol/l) significantly reduced LDL-induced ERK phosphorylation. The calmodulin inhibitor N-(6-aminohexyl)-1-naphthalenesulfonamide (40 µmol/l) significantly decreased ERK phosphorylation induced by all types of LDL. Downregulation of PKC with phorbol myristate acetate (5 µmol/l) markedly reduced LDL-induced ERK phosphorylation. Pretreatment of VSMC with a cell-permeable MEK inhibitor (PD-98059, 40 µmol/l) significantly decreased ERK phosphorylation in response to native and modified LDL. These findings indicate that native and mildly and highly modified LDL utilize similar signaling pathways to phosphorylate ERK and implicate a role for Ca2+/calmodulin, PKC, and MEK. These results suggest a potential link between modified LDL, vascular function, and the development of atherosclerosis in diabetes.

low-density lipoproteins; signal transduction; tyrosine and serine/threonine kinases; calcium/calmodulin; mitogen-activated protein kinase

* V. Velarde and A. J. Jenkins contributed equally to this work.




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