Antisense extracellular signal-regulated kinase-2 gene therapy inhibits platelet-derived growth factor-induced proliferation, migration and transforming growth factor-beta(1) expression in vascular smooth muscle cells and attenuates transplant vasculopathy.
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 G(1) phase to S phase and directed migration, and partially abrogated transforming growth factor-beta(1) (TGF-beta(1)) 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-beta(1) expression and may be a potential therapeutic target for transplant vasculopathy.
Chen
Xi-Lin
XL
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Chen
Zhi-Shui
ZS
Ding
Zhao
Z
Dong
Chong
C
Guo
Hui
H
Gong
Nian-Qiao
NQ
D000256:Adenoviridae / Q000235:genetics; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D001025:Aortitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000077214:Becaplermin; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000627:therapeutic use*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D015291:Transforming Growth Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D043925:Angiogenesis Inducing Agents; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D000077214:Becaplermin; D015291:Transforming Growth Factors; D019950:Mitogen-Activated Protein Kinase 1