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Hyperexpression and activation of extracellular signal-regulated kinases (ERK1/2) in atherosclerotic lesions of cholesterol-fed rabbits.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2000 Jan; Vol. 20 (1), pp. 18-26. - Publication Year :
- 2000
-
Abstract
- A hallmark of hyperlipidemia-induced atherosclerosis is altered gene expression that initiates cell proliferation and (de)differentiation in the intima of the arterial wall. The molecular signaling that mediates this process in vivo has yet to be identified. Extracellular signal-regulated kinases (ERKs) are thought to play a pivotal role in transmitting transmembrane signals required for cell proliferation in vitro. The present studies were designed to investigate the activity, abundance, and localization of ERK1/2 in atherosclerotic lesions of cholesterol-fed rabbits. Immunofluorescence analysis revealed abundant and heterogeneous distribution of ERK1/2, mainly localized in the cap and basal regions of atheromas. A population of ERK-enriched cells was identified as alpha-actin-positive smooth muscle cells (SMCs). ERK1 and 2 were heavily phosphorylated on tyrosyl residues and coexpressed with proliferating cell nuclear antigen in atherosclerotic lesions. ERK1/2 protein levels in protein extracts from atherosclerotic lesions were 2- to 3-fold higher than the vessels of chow-fed rabbits, and their activities were elevated 3- to 5-fold over those of the normal vessel. SMCs derived from atherosclerotic lesions had increased migratory/proliferative ability and higher ERK activity in response to LDL stimulation compared with cells from the normal vessel. Inhibition of ERK activation by PD98059, a specific inhibitor of mitogen-activated protein kinase kinases (MEK1/2), abrogated LDL-induced SMC proliferation in vitro. Taken together, our findings support the proposition that persistent activation and hyperexpression of ERK1/2 may be a critical element to initiate and perpetuate cell proliferation during the development of atherosclerosis.
- Subjects :
- Animals
Arteriosclerosis etiology
Arteriosclerosis pathology
Cell Division
Cholesterol, Dietary administration & dosage
Disease Models, Animal
Enzyme Activation
Gene Expression
Hypercholesterolemia complications
Hypercholesterolemia enzymology
Male
Mitogen-Activated Protein Kinase 1 genetics
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases genetics
Muscle, Smooth, Vascular enzymology
Muscle, Smooth, Vascular pathology
Rabbits
Arteriosclerosis enzymology
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1079-5642
- Volume :
- 20
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 10634796
- Full Text :
- https://doi.org/10.1161/01.atv.20.1.18