© 1999 American Heart Association, Inc.
Original Contribution |
Troponin I Degradation and Covalent Complex Formation Accompanies Myocardial Ischemia/Reperfusion Injury
From the Department of Physiology, Queen's University, Kingston, Ontario, Canada.
Correspondence to Dr J.E. Van Eyk, Department of Physiology, Room 429 Botterell Hall, Queen's University, Kingston, Ontario, Canada K7L 3N6. E-mail jve1{at}post.queensu.ca
Abstract—Selective troponin I (TnI) modification has been demonstrated to be in part responsible for the contractile dysfunction observed with myocardial ischemia/reperfusion injury. We have isolated and characterized modified TnI products in isolated rat hearts after 0, 15, or 60 minutes of ischemia followed by 45 minutes of reperfusion using affinity chromatography with cardiac troponin C (TnC) and an anti-TnI antibody, immunological mapping, reversed-phase high-performance liquid chromatography, and mass spectrometry. Rat cardiac TnI becomes progressively degraded from 210 amino acid residues to residues 1–193, 63–193, and 73–193 with increased severity of injury. Degradation is accompanied by formation of covalent complexes between TnI 1–193 and, respectively, TnC residues 1–94 and troponin T (TnT) residues 191–298. The covalent complexes are likely a result of isopeptide bond formation between lysine 193 of TnI and glutamine 191 of TnT by the cross-linking enzyme transglutaminase. With severe ischemia, cellular necrosis results in specific release of TnI 1–193 into the reperfusion effluent and TnT degradation in the myocardium (25-, 27-, and 33-kDa products). Two-dimensional electrophoresis demonstrated that phosphorylation of TnI prevents ischemia-induced degradation. This study characterized the modified TnI products in isolated rat hearts reperfused after a brief or severe period of ischemia, revealing the progressive nature of TnI degradation, changes in phosphorylation, and covalent complexes with ischemia/reperfusion injury. Finally, we propose a model for ischemia/reperfusion injury in which the extent of proteolytic and transglutaminase activities ultimately determines whether apoptosis or necrosis is achieved.
Key Words: protein degradation • myocardial ischemia • myofilament • troponin I • transglutaminase
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