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Cardioprotection by a novel recombinant serine protease inhibitor in myocardial ischemia and reperfusion injury.
J Pharmacol Exp Ther. 1995 Sep; 274(3):1246-53.JP

Abstract

Polymorphonuclear neutrophils (PMN) play an important role in myocardial ischemia/reperfusion (MI/R) injury; however, the role of neutrophilic proteases is less understood. The effects of a novel serine protease inhibitor (serpin), LEX032, were investigated in a murine model of MI (20 min) and R (24 hr) injury in vivo. LEX032 is a recombinant human alpha 1-antichymotrypsin in which six amino acid residues were replaced around the active center with those of alpha-1 protease inhibitor. LEX032 has the ability to inhibit both neutrophil elastase and cathepsin G, two major neutral serine proteases in neutrophils, as well as superoxide generation. LEX032 (25 or 50 mg/kg) administered i.v. 1 min before reperfusion significantly attenuated myocardial necrotic injury evaluated by cardiac creatine kinase loss compared to MI/R rats receiving only vehicle (P < .001). Moreover, cardiac myeloperoxidase activity, an index of PMN accumulation, in the ischemic myocardium was significantly attenuated by LEX032 as compared with rats receiving vehicle (P < .001). LEX032 also moderately attenuated leukotriene B4-stimulated PMN adherence to rat superior mesenteric artery endothelium and markedly diminished superoxide radical release from LTB4-stimulated PMN in vitro. In a glycogen-induced rat peritonitis model, LEX032 (50 mg/kg) significantly attenuated PMN transmigration into the peritoneal cavity in vivo. In conclusion, the recombinant serine protease inhibitor, LEX032, appears to be an effective agent for attenuating MI/R injury by inhibiting neutrophil-accumulation into the ischemic-reperfused myocardium and by inactivating cytotoxic metabolites (proteases and superoxide radical) released from neutrophils.

Authors+Show Affiliations

Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

7562495

Citation

Murohara, T, et al. "Cardioprotection By a Novel Recombinant Serine Protease Inhibitor in Myocardial Ischemia and Reperfusion Injury." The Journal of Pharmacology and Experimental Therapeutics, vol. 274, no. 3, 1995, pp. 1246-53.
Murohara T, Guo JP, Lefer AM. Cardioprotection by a novel recombinant serine protease inhibitor in myocardial ischemia and reperfusion injury. J Pharmacol Exp Ther. 1995;274(3):1246-53.
Murohara, T., Guo, J. P., & Lefer, A. M. (1995). Cardioprotection by a novel recombinant serine protease inhibitor in myocardial ischemia and reperfusion injury. The Journal of Pharmacology and Experimental Therapeutics, 274(3), 1246-53.
Murohara T, Guo JP, Lefer AM. Cardioprotection By a Novel Recombinant Serine Protease Inhibitor in Myocardial Ischemia and Reperfusion Injury. J Pharmacol Exp Ther. 1995;274(3):1246-53. PubMed PMID: 7562495.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardioprotection by a novel recombinant serine protease inhibitor in myocardial ischemia and reperfusion injury. AU - Murohara,T, AU - Guo,J P, AU - Lefer,A M, PY - 1995/9/1/pubmed PY - 1995/9/1/medline PY - 1995/9/1/entrez SP - 1246 EP - 53 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 274 IS - 3 N2 - Polymorphonuclear neutrophils (PMN) play an important role in myocardial ischemia/reperfusion (MI/R) injury; however, the role of neutrophilic proteases is less understood. The effects of a novel serine protease inhibitor (serpin), LEX032, were investigated in a murine model of MI (20 min) and R (24 hr) injury in vivo. LEX032 is a recombinant human alpha 1-antichymotrypsin in which six amino acid residues were replaced around the active center with those of alpha-1 protease inhibitor. LEX032 has the ability to inhibit both neutrophil elastase and cathepsin G, two major neutral serine proteases in neutrophils, as well as superoxide generation. LEX032 (25 or 50 mg/kg) administered i.v. 1 min before reperfusion significantly attenuated myocardial necrotic injury evaluated by cardiac creatine kinase loss compared to MI/R rats receiving only vehicle (P < .001). Moreover, cardiac myeloperoxidase activity, an index of PMN accumulation, in the ischemic myocardium was significantly attenuated by LEX032 as compared with rats receiving vehicle (P < .001). LEX032 also moderately attenuated leukotriene B4-stimulated PMN adherence to rat superior mesenteric artery endothelium and markedly diminished superoxide radical release from LTB4-stimulated PMN in vitro. In a glycogen-induced rat peritonitis model, LEX032 (50 mg/kg) significantly attenuated PMN transmigration into the peritoneal cavity in vivo. In conclusion, the recombinant serine protease inhibitor, LEX032, appears to be an effective agent for attenuating MI/R injury by inhibiting neutrophil-accumulation into the ischemic-reperfused myocardium and by inactivating cytotoxic metabolites (proteases and superoxide radical) released from neutrophils. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/7562495/Cardioprotection_by_a_novel_recombinant_serine_protease_inhibitor_in_myocardial_ischemia_and_reperfusion_injury_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=7562495 DB - PRIME DP - Unbound Medicine ER -