Tuning cardiac performance in ischemic heart disease and failure by modulating myofilament function

Abstract

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.

Green tea extract protects rats against myocardial infarction associated with left anterior descending coronary artery ligation

“…The Tn complex contains three subunits, troponin C (TnC), the Ca 2+ -binding inhibitory subunit troponin I (TnI), and troponin T (TnT), which binds the complex to tropomyosin. Phosphorylation of cTnI and cTnT mediated by protein kinases A and C can modulate myofilament Ca 2+ sensitivity and cross-bridge cycling in the myocardium [7,30]. Covalent modification of cTnI and cTnT is thought to play an essential role in tuning myocardium performance in both normal and diseased hearts [7,19,24,30].…”

“…This surgery results in contractile dysfunction and contributes to the observed progressive thinning of the infarcted wall, ventricular enlargement, and heart failure [18]. Contractile dysfunction during ischemia is partly attributed to the effects of intracellular acidosis on the contractile apparatus [7,30]. Intracellular acidosis and the resultant reduction in myofilament Ca 2+ sensitivity may lead to the decreased contractility associated with myocardial ischemia [24].…”

Generation and Functional Characterization of Knock-in Mice Harboring the Cardiac Troponin I-R21C Mutation Associated with Hypertrophic Cardiomyopathy

“…All TnI isoforms share a high degree of plasticity that provides TnI the ability to adapt suitable conformations with TnC, TnT, and actin-tropomyosin in the presence and absence of calcium (9,11,12). Notably, cardiac TnI (cTnI) is different from the fast and slow skeletal TnI isoforms because it has an additional ϳ30 amino acids in its N terminus (9,11,12).…”

“…Notably, cardiac TnI (cTnI) is different from the fast and slow skeletal TnI isoforms because it has an additional ϳ30 amino acids in its N terminus (9,11,12). The recent emergence of Ͼ60% of the crystal structure of cardiac Tn (cTn) has revealed and confirmed how the many subunit interactions join together to make up the cTn core domain (13).…”

Cardiac Actin Capping Protein Reduction and Protein Kinase C Inhibition Maintain Myofilament Function During Cardioplegic Arrest

“…Alterations in their function, either through genetic changes or post-translational modifications, significantly influences myocardial performance [4][5][6]. It has been noted that cold crystalloid cardioplegia is associated with impaired myofilament activation, and that this depressed contractility may underlie the reduction in myocardial function that characterizes hearts that have been subjected to cold cardioplegic arrest [7].…”