The novel recombinant serpin, lex032, attenuates myocardial
reperfusion injury in cats.
Delyani, John A., Toyoaki Murohara, and Allan M. Lefer.
Department of Physiology, Jefferson Medical College, Thomas
Jefferson University, Philadelphia, PA 19107
APStracts 2:0372H, 1995.
We studied the potential cardioprotective effects of the novel
recombinant serine protease inhibitor (serpin), LEX032, which
inhibits the serine proteases elastase and cathepsin G. LEX032 is a
recombinant construct of human antichymotrypsin in which 6 amino acid
residues were replaced around the active center with those of human
[alpha]1 protease inhibitor. Cats were subjected to 90 minutes of
left anterior descending coronary artery (LAD) occlusion and 270
minutes of reperfusion (MI/R). Either LEX032 or its vehicle (i.e.,
phosphate buffered saline) was administered (i.v.) 10 minutes prior
to reperfusion. Control cats were subjected to sham MI/R. Cats
treated with LEX032 demonstrated a marked reduction in cardiac
necrosis following MI/R compared to cats receiving only vehicle
(10+/-3 % vs 31+/-3 %, p<0.01). In addition, relaxation of LAD
coronary artery rings to the endothelium-dependent dilators (e.g.,
acetylcholine and A23187) was greater in the LEX032 treated group as
compared to the cats receiving vehicle (72+/-5% vs 52+/-7%,
p<0.05 and 74+/-8% vs 50+/-8%, p<0.05, respectively)
indicating that endothelial function was preserved by LEX032.
Moreover, LEX032 administration resulted in a marked reduction of
neutrophil adherence to ex vivo coronary vascular endothelium as
compared to vehicle (33+/-4 PMNs/mm2 vs 86+/-7 PMNs/mm2,
p<0.01). These data indicate that LEX032, is a significant
cardioprotective agent exerting its protective effect by inhibition
of PMN mediated cellular injury, and this agent represents a novel
means of attenuating PMN-mediated reperfusion injury.
Received 24 May 1995; accepted in final form 16 August 1995.
APS Manuscript Number H483-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 August 1995.