Faculty Collaboration Database

Protein kinase C epsilon induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism. Am J Physiol Heart Circ Physiol 2005 Nov;289(5):H1881-8

Date

06/14/2005

Pubmed ID

15951344

DOI

10.1152/ajpheart.00454.2005

Scopus ID

2-s2.0-27144455797 (requires institutional sign-in at Scopus site)   18 Citations

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.

Author List

Montgomery DE, Rundell VL, Goldspink PH, Urboniene D, Geenen DL, de Tombe PP, Buttrick PM

MESH terms used to index this publication - Major topics in bold

Actin Cytoskeleton
Adenosine Triphosphatases
Animals
Animals, Genetically Modified
Cardiotonic Agents
Dobutamine
Electrophoresis, Polyacrylamide Gel
Heart Failure
Mice
Myocardial Contraction
Myocardium
Phosphorylation
Reverse Transcriptase Polymerase Chain Reaction
Sarcomeres
Systole
Ultrasonography