title: Protein kinase C epsilon induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism.
abstract: Myofilament dysfunction is a common point of convergence for many forms of heart failure. Recently, we showed that cardiac overexpression of PKC epsilon initially depresses myofilament activity and then leads to a progression of changes characteristic of human heart failure. Here, we examined the effects of PKC epsilon on contractile reserve, Starling mechanism, and myofilament activation in this model of end-stage dilated cardiomyopathy. Pressure-volume loop analysis and echocardiography showed that the PKC epsilon mice have markedly compromised systolic function and increased end-diastolic volumes. Dobutamine challenge resulted in a small increase in contractility in PKC epsilon mice but failed to enhance cardiac output. The PKC epsilon mice showed a normal length-dependent tension development in skinned cardiac muscle preparations, although Frank-Starling mechanism appeared to be compromised in the intact animal. Simultaneous measurement of tension and ATPase demonstrated that the maximum tension and ATPase were markedly lower in the PKC epsilon mice at any length or Ca2+ concentration. However, the tension cost was also lower indicating less energy expenditure. We conclude 1) that prolonged overexpression of PKC epsilon ultimately leads to a dilated cardiomyopathy marked by exhausted contractile reserve, 2) that PKC epsilon does not compromise the Frank-Starling mechanism at the myofilament level, and 3) that the Starling curve excursion is limited by the inotropic state of the heart. These results reflect the significance of the primary myofilament contractilopathy induced by phosphorylation and imply a role for PKC epsilon-mediated phosphorylation in myofilament physiology and the pathophysiology of decompensated cardiac failure.
authors.affiliation: Department of Medicine, Section of Cardiology, Univ. of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Montgomery
authors.forename: Veronica L M
authors.initials: VL
authors.lastname: Rundell
authors.forename: Paul H
authors.initials: PH
authors.lastname: Goldspink
authors.forename: Dalia
authors.initials: D
authors.lastname: Urboniene
authors.forename: David L
authors.initials: DL
authors.lastname: Geenen
authors.forename: Pieter P
authors.initials: PP
authors.lastname: de Tombe
authors.forename: Peter M
authors.initials: PM
authors.lastname: Buttrick
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D002316:Cardiotonic Agents / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006333:Heart Failure / Q000139:chemically induced* / Q000000981:diagnostic imaging; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D013599:Systole; D014463:Ultrasonography
chemical_list: D002316:Cardiotonic Agents; D004280:Dobutamine; D000251:Adenosine Triphosphatases