Tuning cardiac performance in ischemic heart disease and failure by modulating myofilament function.
The cardiac myofilaments are composed of highly ordered arrays of proteins that coordinate cardiac contraction and relaxation in response to the rhythmic waves of [Ca(2+)] during the cardiac cycle. Several cardiac disease states are associated with altered myofilament protein interactions that contribute to cardiac dysfunction. During acute myocardial ischemia, the sensitivity of the myofilaments to activating Ca(2+) is drastically reduced, largely due to the effects of intracellular acidosis on the contractile machinery. Myofilament Ca(2+) sensitivity remains compromised in post-ischemic or "stunned" myocardium even after complete restoration of blood flow and intracellular pH, likely because of covalent modifications of or proteolytic injury to contractile proteins. In contrast, myofilament Ca(2+) sensitivity can be increased in chronic heart failure, owing in part to decreased phosphorylation of troponin I, the inhibitory subunit of the troponin regulatory complex. We highlight, in this paper, the central role of the myofilaments in the pathophysiology of each of these distinct disease entities, with a particular focus on the molecular switch protein troponin I. We also discuss the beneficial effects of a genetically engineered cardiac troponin I, with a histidine button substitution at C-terminal residue 164, for a variety of pathophysiologic conditions, including hypoxia, ischemia, ischemia-reperfusion and chronic heart failure.
Day
Sharlene M
SM
Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, 7301 MSRB III, Ann Arbor, MI 48109-0644, USA. sday@umich.edu
Westfall
Margaret V
MV
Metzger
Joseph M
JM
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D019210:Troponin I / Q000378:metabolism
D019210:Troponin I; D002118:Calcium