The role of c-jun in PDTC-sensitive flow-dependent restenosis after angioplasty and stenting.
Restenosis after balloon angioplasty and stenting is exacerbated by low flow. Flow-dependent restenosis after angioplasty but not stenting is prevented by the antioxidant pyrrolidine dithiocarbamate (PDTC). c-jun may play a role in these events as AP-1 activity is both flow and redox sensitive. Carotid arteries of cholesterol fed rabbits underwent stenting or balloon injury in the presence of low or normal flow. c-jun mRNA expression was enhanced by low flow and injury (stent>balloon) and inhibited by the antioxidant PDTC irrespective of the injury type. The effect of locally delivered DZ13 (a DNAzyme specific for c-jun) or scrambled DZ13 (inactive DNAzyme) was assessed by histomorphometry at 28 days. Low flow significantly increased intimal hyperplasia in B and S relative to normal flow (P<0.05). The active DNAzyme DZ13 markedly reduced intimal hyperplasia (P<0.001) and increased lumen size (P<0.05) in balloon-injured but not in stented segments, and abrogated the effect of low flow on restenosis after angioplasty, similar to the morphological effects of PDTC. We conclude that c-jun expression is enhanced by low flow and by injury (stent>balloon) and markedly attenuated by PDTC, and that c-jun is an important mediator of flow-dependent restenosis in balloon-injured but not stented vessels.
Murrell
Melanie
M
Department of Cardiology, Royal North Shore Hospital, Australia.
Khachigian
Levon
L
Ward
Michael R
MR
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000502:physiology*; D017536:Carotid Artery, Common / Q000503:physiopathology*; D016893:Carotid Stenosis / Q000503:physiopathology*; D023903:Coronary Restenosis / Q000503:physiopathology; D021881:DNA, Catalytic / Q000494:pharmacology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D016758:Genes, jun / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D011817:Rabbits; D015607:Stents / Q000009:adverse effects; D013859:Thiocarbamates / Q000494:pharmacology
D000975:Antioxidants; D021881:DNA, Catalytic; C485475:Dz13 DNAzyme; D016755:Proto-Oncogene Proteins c-jun; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid