Hyperexpression and Activation of Extracellular Signal–Regulated Kinases (ERK1/2) in Atherosclerotic Lesions of Cholesterol-Fed Rabbits

Abstract

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 ␣-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.

The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKCε inhibition

“…ERK1͞2, in particular, is clearly up-regulated in vivo in atherosclerosis (24) as well as in IL-1 (13)-and PMA (20)-induced COX-2 expression. Therefore, we examined whether DHA affected IL-1 and PMA-induced ERK1͞2 activation.…”

The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell Proliferation

“…The Ras 3 Raf 3 MEK 3 MAPK pathway is strongly activated during neointimal SMC proliferation in atherosclerotic lesions (49). In addition, ERK-MAPK signaling is induced by stimulation of quiescent SMC with PDGF and has been characterized as a key signaling pathway involved in SMC proliferation (50,51).…”

Epidermal Growth Factor and Perlecan Fragments Produced by Apoptotic Endothelial Cells Co-Ordinately Activate ERK1/2-Dependent Antiapoptotic Pathways in Mesenchymal Stem Cells

“…Activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway and Bcl-xL upregulation within aSMA-positive neointimal cells are key molecular components implicated in the development of this antiapoptotic phenotype [24][25][26][27][28]. In a murine aortic CTV model, ex vivo gene transfer of ERK2 antisense oligonucleotides decreases the number of aSMA-positive cells accumulating within neointimal areas [26].…”