BACKGROUND: The contribution of the sarcomere's thin filament to the contractile dysfunction of human cardiomyopathy is not well understood. METHODS AND RESULTS: We have developed techniques to isolate and functionally characterize intact (native) thin filaments obtained from failing and nonfailing human ventricular tissue. By use of in vitro motility and force assays, native thin filaments from failing ventricular tissue exhibited a 19% increase in maximal velocity but a 27% decrease in maximal contractile force compared with nonfailing myocardium. Native thin filaments isolated from human myocardium after left ventricular assist device support demonstrated a 37% increase in contractile force. Dephosphorylation of failing native thin filaments resulted in a near-normalization of thin-filament function, implying a phosphorylation-mediated mechanism. Tissue expression of the protein kinase C isoforms alpha, beta1, and beta2 was increased in failing human myocardium and reduced after left ventricular assist device support. CONCLUSIONS: These novel findings demonstrate that (1) the thin filament is a key modulator of contractile performance in the failing human heart, (2) thin-filament function is restored to near normal levels after LVAD support, and (3) the alteration of thin-filament function in failing human myocardium is mediated through phosphorylation, most likely through activation of protein kinase C.
BACKGROUND: The contribution of the sarcomere's thin filament to the contractile dysfunction of humancardiomyopathy is not well understood. METHODS AND RESULTS: We have developed techniques to isolate and functionally characterize intact (native) thin filaments obtained from failing and nonfailing human ventricular tissue. By use of in vitro motility and force assays, native thin filaments from failing ventricular tissue exhibited a 19% increase in maximal velocity but a 27% decrease in maximal contractile force compared with nonfailing myocardium. Native thin filaments isolated from human myocardium after left ventricular assist device support demonstrated a 37% increase in contractile force. Dephosphorylation of failing native thin filaments resulted in a near-normalization of thin-filament function, implying a phosphorylation-mediated mechanism. Tissue expression of the protein kinase C isoforms alpha, beta1, and beta2 was increased in failing human myocardium and reduced after left ventricular assist device support. CONCLUSIONS: These novel findings demonstrate that (1) the thin filament is a key modulator of contractile performance in the failing human heart, (2) thin-filament function is restored to near normal levels after LVAD support, and (3) the alteration of thin-filament function in failing human myocardium is mediated through phosphorylation, most likely through activation of protein kinase C.
Authors: David Hefer; Ting Yi; Donald E Selby; David E Fishbaugher; Sarah M Tremble; Kelly J Begin; Prospero Gogo; Martin M Lewinter; Markus Meyer; Bradley M Palmer; Peter Vanburen Journal: J Mol Cell Cardiol Date: 2011-10-14 Impact factor: 5.000
Authors: Tomas Rajtik; Eva Goncalvesova; Zoltan V Varga; Przemyslaw Leszek; Mariusz Kusmierczyk; Michal Hulman; Jan Kyselovic; Peter Ferdinandy; Adriana Adameova Journal: Am J Transl Res Date: 2017-08-15 Impact factor: 4.060
Authors: Paul J M Wijnker; Vasco Sequeira; E Rosalie Witjas-Paalberends; D Brian Foster; Cristobal G dos Remedios; Anne M Murphy; Ger J M Stienen; Jolanda van der Velden Journal: Arch Biochem Biophys Date: 2014-05-09 Impact factor: 4.013
Authors: Sarah E Lang; Jennifer Schwank; Tamara K Stevenson; Mark A Jensen; Margaret V Westfall Journal: J Mol Cell Cardiol Date: 2014-12-03 Impact factor: 5.000