Novel recombinant serpin, LEX-032, attenuates myocardial reperfusion injury in cats.
We studied the potential cardioprotective effects of the novel recombinant serine protease inhibitor (serpin), LEX-032, which inhibits the serine proteases elastase and cathepsin G. LEX-032 is a recombinant construct of human alpha 1-antichymotrypsin in which six amino acid residues were replaced around the active center with those of human alpha 1-protease inhibitor. Cats were subjected to 90 min of left anterior descending coronary artery (LAD) occlusion and 270 min of reperfusion (MI/R). Either LEX-032 or its vehicle (i.e., phosphate-buffered saline) was administered intravenously 10 min before reperfusion. Control cats were subjected to sham MI/R. Cats treated with LEX-032 demonstrated a marked reduction in cardiac necrosis after MI/R compared with cats receiving only vehicle (10 +/- 3 vs. 31 +/- 3%, P < 0.01). In addition, relaxation of LAD rings to the endothelium-dependent dilators (e.g., acetylcholine and A23187) was greater in the LEX-032-treated group than in 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 LEX-032. Moreover, LEX-032 administration resulted in a marked reduction of polymorphonuclear leukocyte (PMN) adherence to ex vivo coronary vascular endothelium compared with vehicle (33 +/- 4 vs. 86 +/- 7 PMNs/mm2, P < 0.01). These data indicate that LEX-032 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.
Delyani
J A
JA
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Murohara
T
T
Lefer
A M
AM
D000818:Animals; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007962:Leukocytes / Q000473:pathology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000008:administration & dosage; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage*; D015843:Serpins / Q000008:administration & dosage*
C095800:LEX 032; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D015843:Serpins