Antisense oligonucleotide inhibition of PDGFR-beta receptor subunit expression directs suppression of intimal thickening.
BACKGROUND
The elucidation of molecular mechanisms of vascular cell biology has markedly influenced our thinking on the pathophysiology of vascular disease. Antisense oligonucleotide gene therapy has helped identify proteins critical to cell-cycle progression and proliferation and possible therapeutic strategies to combat human disease. This approach, however, has not yet been used to examine the contribution of chemotactic proteins and/or their receptors. Platelet-derived growth factor-BB (PDGF-BB) released from activated platelets adherent to subendothelial connective tissue is a principal smooth muscle cell chemotactic factor.


RESULTS
A series of experiments was performed to assess the capacity of antisense oligonucleotides to reduce PDGF-beta receptor subunit (PDGFR-beta) expression and the contribution of PDGFR-beta in neointimal formation. Sustained, direct, and local perivascular administration of two different antisense oligonucleotide sequences complementary to PDGFR-beta mRNA almost completely abolished the expression of PDGFR-beta protein in the intima and media of injured carotid arteries and decreased neointimal formation by 80% and 60%, respectively. Furthermore, neointimal formation correlated precisely with PDGFR-beta expression in an exponential fashion.


CONCLUSIONS
Thus, myointimal proliferation depends on both PDGFR-beta overexpression and its activation by PDGF-BB. Removal of either of these two elements can suppress neointimal formation.
Sirois
M G
MG
Harvard-MIT Division of Health Sciences and Technology, Cambridge, Brigham and Women's Hospital (E.R.E.), Boston, Mass, USA. mgsirois@mit.edu
Simons
M
M
Edelman
E R
ER
D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology*
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor