Published online before print October 9, 2003, doi: 10.1161/01.RES.0000099889.35340.6F
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© 2003 American Heart Association, Inc.
Molecular Medicine |
C-Terminal Truncation of Cardiac Troponin I Causes Divergent Effects on ATPase and Force
Implications for the Pathophysiology of Myocardial Stunning
From the Department of Biochemistry (D.B.F., J.E.V.E.), Queen’s University, Kingston, Ontario, Canada; Cardiology Unit (T.N., P.V.), Department of Medicine, University of Vermont, Burlington, Vt; Department of Pediatrics (A.M.), Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md; and Department of Physiology (J.E.V.E.), Queen’s University, Kingston, Ontario, Canada. Present address for D.B.F. is Boston Biomedical Research Institute, Watertown, Mass.
Correspondence to Dr Jennifer E. Van Eyk, Department of Physiology, Queen’s University, 3rd Floor Botterell Hall, Stuart St, Kingston, Ontario, Canada K7L 3N6. E-mail jve1{at}post.queensu.ca
Myocardial stunning is a form of reversible myocardial ischemia/reperfusion injury associated with systolic and diastolic contractile dysfunction. In the isolated rat heart model, myocardial stunning is characterized by specific C-terminal proteolysis of the myofilament protein, troponin I (cTnI) that yields cTnI1-193. To determine the effect of this particular C-terminal truncation of cTnI, without the confounding factor of other stunning-induced protein modifications, a series of solution biochemical assays has been undertaken using the human homologue of mouse/rat cTnI1-193, cTnI1-192. Affinity chromatography and actin sedimentation experiments detected little, or no, difference between the binding of cTnI (cTnI1-209) and cTnI1-192 to actin-tropomyosin, troponin T, or troponin C. Both cTnI and cTnI1-192 inhibit the actin-tropomyosin–activated ATPase activity of myosin subfragment 1 (S1), and this inhibition is released by troponin C in the presence of Ca2+. However, cTnI1-192, when reconstituted as part of the troponin complex (cTn1-192), caused a 54±11% increase in the maximum Ca2+-activated actin-tropomyosin-S1 ATPase activity, compared with troponin reconstituted with cTnI (cTn). Furthermore, cTn1-192 increased Ca2+ sensitivity of both the actin-tropomyosin-activated S1 ATPase activity and the Ca2+-dependent sliding velocity of reconstituted thin filaments, in an in vitro motility assay, compared with cTn. In an in vitro force assay, the actin-tropomyosin filaments bearing cTn1-192 developed only 76±4% (P<0.001) of the force obtained with filaments composed of reconstituted cTn. We suggest that cTnI proteolysis may contribute to the pathophysiology of myocardial stunning by altering the Ca2+-sensing and chemomechanical properties of the myofilaments.
Key Words: troponin • myocardial stunning • force-ATPase relation • heart failure
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