Abstract 413: A Dominant Negative Mutant of Plasminogen Activator Inhibitor-1 Does Not Inhibit Intimal Hyperplasia After Balloon Coronary Angioplasty in Pigs
Background. Plasminogen activator inhibitor 1 (PAI-1) regulates arterial remodeling and intimal hyperplasia after vascular injury. PAI-1-R is a recombinant mutant that completely lacks anti-protease activity yet binds vitronectin (VN) with normal affinity. PAI-1-R inhibits cell migration in vitro and neointima formation in rodents by binding VN and competitively blocking its binding to integrins.
Objective and Methods. To determine if PAI-1-R inhibits intimal hyperplasia under experimental conditions highly relevant to human coronary artery disease we performed balloon angioplasty of the left circumflex coronary artery (LCX) of male pigs and administered PAI-1-R by direct coronary infusion immediately after angioplasty and by peripheral intravenous infusion on each of the next two days (5 mg/infusion; total dose 15 mg/pig). Thirteen pigs (weight 24±4.3 kg) received PAI-1-R and 13 pigs (weight 24 ± 4.7 kg) received identical infusions of vehicle control. Animals were euthanized 14 days after angioplasty and neointima formation in the injured LCX was determined by microscopic morphometric analysis.
Results. Plasma PAI-1-R concentrations assessed 1 hr after each infusion were 32±18, 89±60, and 59±16 ng/mL, respectively, in PAI-1-R-treated pigs and undetectable in controls. There was no significant difference in LCX neointima formation between PAI-1-R- vs. vehicle-treated pigs (maximal intima thickness 523±47 vs. 581±49 μm, p=0.41; intima area/media area normalized to media rupture length 3.7±0.3 vs 3.8±0.3, p=0.8).
Conclusion. Short-term, bolus infusions of a dominant negative form of PAI-1 do not significantly inhibit neointima formation in pigs after coronary angioplasty. These results contrast with rodent data and suggest that alternative strategies that achieve higher concentrations of PAI-1-R at vascular injury sites will be required to assess the efficacy of this strategy under clinically relevant conditions.
- © 2012 by American Heart Association, Inc.