Published online before print October 9, 2003, doi: 10.1161/01.RES.0000099889.35340.6F
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Submitted on October 28, 2002
Revised on September 18, 2003
Accepted on September 25, 2003
C-Terminal Truncation of Cardiac Troponin I Causes Divergent Effects on ATPase and Force. Implications for the Pathophysiology of Myocardial Stunning
D. Brian Foster ;
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.
* To whom correspondence should be addressed. 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 the 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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