A DNA enzyme against plasminogen activator inhibitor- type 1 (PAI-1) limits neointima formation after angioplasty in an obese diabetic rodent model.
We investigated whether targeted cleavage of PAI-1 mRNA might prevent post-angioplasty neointima formation in diabetic JCR:LA-cp/cp rats with naturally elevated PAI-1 levels. Catalytic DNA enzymes targeting rat PAI-1 mRNA (PAI-1 DNA enzyme, n = 12) or a random sequence as control (scrambled DNA enzyme, n = 12) were infused at the site of arterial damage. Control animals demonstrated prominent PAI-1 protein expression in the arterial endothelium at 48 hours, and robust neointimal proliferation by two weeks, with 60 +/- 10% mean occlusion of the artery lumen. The neointimal lesion consisted of dense fibrin deposition and numerous proliferating smooth muscle cells, as determined by dual alpha-smooth muscle actin/Ki67 expression. Treatment with PAI-1 DNA enzyme resulted in marked early (48 hour) reduction of endothelial PAI-1 protein expression, which persisted for the next two weeks as well as a two fold reduction of expression of PAI-1 mRNA by RT-PCR at the same time point, (P < 0.05). By two weeks, PAI-1 DNA enzyme treated animals demonstrated significantly reduced levels of fibrin deposition and 5-fold lower levels of proliferating smooth muscle cells at the site of arterial injury compared to controls (P < 0.01), and a 2-fold lower neointima/media ratio (0.67 +/- 0.11 vs 1.39 +/- 0.12) (P < 0.05). Treatment with a catalytic PAI-1 DNA enzyme successfully prevents neointimal proliferation after balloon injury in diabetic animals.
Witkowski
Piotr
P
Department of Surgery, Columbia University, College of Surgeons and Physicians, New York, New York, USA. pw2004@columbia.edu
Seki
Tetsunori
T
Xiang
Guosheng
G
Martens
Timothy
T
Sondermeijer
Hugo
H
See
Fiona
F
Bhagat
Govind
G
Schuster
Michael
M
Hardy
Mark A
MA
Itescu
Silviu
S
D000199:Actins / Q000032:analysis; D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D000818:Animals; D021881:DNA, Catalytic / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D007269:Injections, Intra-Arterial; D019394:Ki-67 Antigen / Q000032:analysis; D009130:Muscle, Smooth / Q000737:chemistry; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
D000199:Actins; D021881:DNA, Catalytic; D019394:Ki-67 Antigen; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D005337:Fibrin