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Titolo:
Activation of MAPK by modified low-density lipoproteins in vascular smoothmuscle cells
Autore:
Velarde, V; Jenkins, AJ; Christopher, J; Lyons, TJ; Jaffa, AA;
Indirizzi:
Med Univ S Carolina, Div Endocrinol Diabet Med Genet, Dept Med, Charleston, SC 29425 USA Med Univ S Carolina Charleston SC USA 29425 Med, Charleston, SC 29425 USA Med Univ S Carolina, Div Endocrinol Diabet Med Genet, Dept Pharmacol, Charleston, SC 29425 USA Med Univ S Carolina Charleston SC USA 29425 col, Charleston, SC 29425 USA
Titolo Testata:
JOURNAL OF APPLIED PHYSIOLOGY
fascicolo: 3, volume: 91, anno: 2001,
pagine: 1412 - 1420
SICI:
8750-7587(200109)91:3<1412:AOMBML>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROLIFERATION; GROWTH; ATHEROSCLEROSIS; CALMODULIN; CALCIUM; PHOSPHORYLATION; SUPPRESSION; GLYCATION; PATHWAYS; HEPARIN;
Keywords:
low-density lipoproteins; signal transduction; tyrosine and serine/threonine kinases; calcium/calmodulin; mitogen-activated protein kinase;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Jaffa, AA Med Univ S Carolina, Div Endocrinol Diabet Med Genet, Dept Med, 114 Doughty St,POB 250776, Charleston, SC 29425 USA Med Univ S Carolina 114Doughty St,POB 250776 Charleston SC USA 29425
Citazione:
V. Velarde et al., "Activation of MAPK by modified low-density lipoproteins in vascular smoothmuscle cells", J APP PHYSL, 91(3), 2001, pp. 1412-1420

Abstract

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 mug/mlto 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 mmol/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 mu mol/l) significantly decreased ERK phosphorylation induced by all types of LDL. Downregulation of PKC with phorbol myristate acetate (5 mmol/l) markedly reduced LDL-induced ERK phosphorylation. Pretreatment of VSMC with a cell-permeable MEK inhibitor (PD-98059, 40 mu mol/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.

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Documento generato il 14/08/20 alle ore 04:54:30