Journal
CIRCULATION RESEARCH
Volume 93, Issue 10, Pages 917-924Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000099889.35340.6F
Keywords
troponin; myocardial stunning; force-ATPase relation; heart failure
Funding
- NHLBI NIH HHS [R01 HL 63038] Funding Source: Medline
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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 cTnI(1-193). 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 cTnI(1-193), cTnI(1-192). Affinity chromatography and actin sedimentation experiments detected little, or no, difference between the binding of cTnI (cTnI(1-209)) and cTnI(1-192) to actin-tropomyosin, troponin T, or troponin C. Both cTnI and cTnI(1-192) 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, cTnI(1-192), when reconstituted as part of the troponin complex (cTn(1-192)), caused a 54+/-11% increase in the maximum Ca2+-activated actin-tropomyosin-S1 ATPase activity, compared with troponin reconstituted with cTnI (cTn). Furthermore, cTn(1-192) 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 cTn(1-192) 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.
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