Antisense extracellular signal-regulated kinase-2 gene therapy inhibits platelet-derived growth factor-induced proliferation, migration and transforming growth factor-β₁expression in vascular smooth muscle cells and attenuates transplant vasculopathy

Abstract

Summary Platelet‐derived growth factor‐BB (PDGF‐BB) enables vascular smooth muscle cells (VSMCs) to proliferate, migrate and secrete connective tissue matrix, which are critical events in transplant vasculopathy. However, little is known about the intracellular pathways that mediate these biologic responses of VSMCs. Extracellular signal‐regulated kinase (ERK) pathway plays a major role in cellular responses and vascular diseases. In this study, we observed that the inhibition of ERK2 activity by recombinant adenovirus encoding antisense ERK2 (Adanti‐ERK2) significantly suppressed the proliferation, converting of cell cycle from G1 phase to S phase and directed migration, and partially abrogated transforming growth factor‐β1 (TGF‐β1) expression in VSMCs stimulated with PDGF‐BB. Ex vivo gene transfer of Adanti‐ERK2 into rat aortic allograft attenuated chronic transplant vasculopathy by the inhibition of VSMC proliferation and migration. In conclusion, ERK2 is involved in PDGF‐BB‐induced VSMCs proliferation, migration and TGF‐β1 expression and may be a potential therapeutic target for transplant vasculopathy.

The Perlecan Fragment LG3 Is a Novel Regulator of Obliterative Remodeling Associated With Allograft Vascular Rejection

“…30 The present results further support an important role for ERK 1/2 activation in immune-mediated vascular remodeling as we demonstrated progressive neointima formation in association with ERK1/2 phosphorylation in neointimal cells of allogeneic aortic allografts. However, mediators inducing ERK1/2 activation in neointimal cells during VR are still incompletely defined.…”

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

“…Biochemical inhibition of ERK1/2 activation in hMSC exposed to SSC largely prevents Bcl-xL upregulation and blocks the antiapoptotic response in hMSC. ERK1/2 activation and Bcl-xL upregulation play central roles in neointima formation in most, if not all, forms of vascular remodeling [24][25][26][27][28]. Hence, the present results demonstrate that mediators from apoptotic EC induce antiapoptotic cross-talk in hMSC that recapitulate key features of the neointimal phenotype.…”

“…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]. Increased ERK1/2 activation has also been documented within neointimal cells in classical atherosclerotic models [27,28].…”

TGF-β suppresses the upregulation of MMP-2 by vascular smooth muscle cells in response to PDGF-BB

“…Whereas PDGF-BB has been previously shown to affect TGF-␤ isoform expression in SMCs (15,59,82) and other cells (75,77), this is the first demonstration that, in VSMCs, the TGF-␤ isoforms are reciprocally regulated. It should be noted that the 33% decrease in total active TGF-␤ levels observed here only reflected the contributions of TGF-␤1 and TGF-␤2 (Fig.…”