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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/H29    most recent 00482.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shaw, E. E. Articles by Pyle, W. G. PubMed PubMed Citation Articles by Shaw, E. E. Articles by Pyle, W. G.

Relaxin alters cardiac myofilament function through a PKC-dependent pathway

¹Department of Biomedical Sciences, Ontario Veterinary College, and ²Biophysics Interdepartmental Group, University of Guelph, Guelph, Ontario, Canada

Submitted 8 May 2008 ; accepted in final form 23 April 2009

The pregnancy hormone relaxin (RLX) is a powerful cardiostimulatory peptide. Despite its well-characterized effects on the heart, the intracellular mechanisms responsible for RLX's positive inotropic effects are unknown. Cardiac myofilaments are the central contractile elements of the heart, and changes in the phosphorylation status of myofilament proteins are known to mediate changes in function. The first objective of this study was to determine whether RLX stimulates myofilament activation and alters the phosphorylation of one or more myofilament proteins. RLX works through a variety of intracellular signaling cascades in different tissue types. Protein kinases A (PKA) and C (PKC) are two common molecules implicated in RLX signaling and are known to affect myofilament function. Thus the second objective of this study was to determine whether RLX mediates its myocardial effects through PKA or PKC activation. Murine myocardium was treated with recombinant H2-RLX, and cardiac myofilaments were isolated. RLX increased cardiac myofilament force development at physiological levels of intracellular Ca²⁺ without altering myofilament ATP consumption. Myosin binding protein C, troponin T, and troponin I phosphorylation levels were increased with RLX treatment. Immunoblot analysis revealed an increase in myofilament-associated PKC-, decreases in PKC- and -β_II, but no effect on PKC-. Inhibition of PKC with chelerythrine chloride or PKC- with rottlerin prevented the RLX-dependent changes in myofilament function and protein phosphorylation. PKA antagonism with H-89 had no effect on the myofilament effects of RLX. This study is the first to show that RLX-dependent changes in myofilament-associated PKC alters myofilament activation in a manner consistent with its cardiostimulatory effects.

heart; ventricular myocardium; hormone; phosphorylation; intracellular signaling