Effect of contractile protein alterations on cardiac myofilament function in human heart failure
Year: 2006
Type: dissertation
Abstract: The main objective of this thesis was to elucidate the effect of translational and post-translational alterations in contractile proteins occurring during heart failure on contractile function in human cardiac tissue. Isometric force and ATPase activity measurements were performed in skinned human cardiac trabeculae and muscle strips; force was measured in cardiac myofibrils and cardiomyocytes. The technique of troponin complex exchange was validated for human cardiomyocytes. To establish the link between altered protein composition and functional properties of cardiac tissue analysis of contractile protein composition was performed using one-dimensional SDS polyacrylamide gel electrophoresis and Western immunoblot analysis. The shift of alpha- to beta-MHC isoform was studied as an example of translational changes because this is a prominent feature in animal models of heart failure. The rate of ATP consumption of preparations with pure (100 %) alpha-MHC was approximately 5 times higher than the rate in preparations with pure beta-MHC. The Ktr associated with pure alpha-MHC expression calculated from the regression line was considerably higher than the values obtained in ventricular tissue. These results indicate that even a small shift in MHC isoform expression may have a considerable impact on cardiac performance in human tissue. The degradation of cTnI from its C-terminus was investigated as post-translation modification in failing myocardium, important during cardiac stunning and in remodeled non-infarcted heart. Cardiac TnI degradation does not affect beta-adrenergic and preload-dependent responses in human myocardium, but may contribute to diastolic dysfunction in human myocardium. The questions addressed in this thesis provide an insight into the cellular pathomechanisms of depressed contractility in human heart failure. The information about the role of MHC isoforms and cTnI obtained in these studies is important for the development of new protein targeted therapeutic interventions, which will improve treatment and decrease mortality of heart failure in humans.
Author: N.A. Narolska
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2113470758