Down-regulation of the ERK1 and ERK2 mitogen-activated protein kinases using antisense oligonucleotides inhibits intimal hyperplasia in a porcine model of coronary balloon angioplasty.
OBJECTIVE
Neointimal hyperplasia is a central feature in the pathogenesis of a variety of vascular pathologies. Mitogen-activated protein kinases (MAPK) are involved in the downstream transduction of signals from receptors for many of the molecules known to be instrumental in this process and thus represent a potential target for the modification of the proliferative response. We examined the hypothesis that down-regulation of MAPK would inhibit neointima formation in a porcine coronary injury model.


METHODS
Balloon angioplasty was performed on 38 coronary arteries from 23 large white pigs. Antisense oligonucleotides to the p42 and p44 MAPK were locally delivered to the site of injury immediately after balloon injury. At 7 or 21 days, arteries were harvested for morphometry, determination of cell proliferation and assessment of MAPK protein levels.


RESULTS
At 7 days, neointima formation was significantly reduced compared to controls (corrected intima/media ratio (IMR) 1.01+/-0.13 vs. 1.61+/-0.07, P<0.01) and this was associated with a 58% and 23% down-regulation of p42 and p44 protein levels, respectively. Intimal and medial proliferation rates were also reduced by 32% and 26%, respectively. At 21 days however, the effect of the treatment on MAPK protein levels was no longer significant and this correlated with a loss of the effects on IMR and cell proliferation.


CONCLUSIONS
Down-regulation of MAPK inhibits early smooth muscle cell (SMC) proliferation and neointimal thickening in response to arterial injury, implying that it plays an important role in determining the early vascular response to injury. Inhibitory effects were less apparent at 21 days after a single delivery of oligonucleotide, implying that more sustained local delivery may be required to achieve longer term therapeutic benefit.
Liu
Bo
B
Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Fisher
Michael
M
Groves
Peter
P
D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D006965:Hyperplasia; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D013552:Swine; D017539:Tunica Intima / Q000473:pathology*
D016376:Oligonucleotides, Antisense; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases