2-hydroxyoleic acid affects cardiomyocyte [Ca2+]i transient and contractility in a region-dependent manner.
Monounsaturated fatty acids such as oleic acid are cardioprotective, modify the physicochemical properties of cardiomyocyte membranes, and affect the electrical stability of these cells by regulating the conductance of ion channels. We have designed a nonhydrolysable oleic acid derivative, 2-hydroxyoleic acid (2-OHOA), which regulates membrane lipid structure and cell signaling, resulting in beneficial cardiovascular effects. We previously demonstrated that 2-OHOA induces PKA activation and PKCalpha translocation to the membrane; both pathways are thought to regulate transient outward K(+) current (I(to)) depending on the stimulus and the species used. This study was designed to investigate the effect of 2-OHOA on isolated cardiomyocytes. We examined the dose- and time-dependent effect of 2-OHOA on cytosolic Ca(2+) concentration ([Ca(2+)](i)) transient and contraction of myocytes isolated from different parts of the rat ventricular myocardium. Although this drug had no effect on [Ca(2+)](i) transient and cell shortening in myocytes isolated from the septum, it increased (up to 95%) [Ca(2+)](i) transient and cell shortening in subpopulations of myocytes from the right and left ventricles. The pattern of the effects of 2-OHOA was similar to that observed following the application of the I(to) blocker 4-aminopyridine, suggesting that the drug may act on this channel. Unlike the effect of 2-OHOA on [Ca(2+)](i) transient and cell shortening, PKCalpha translocation to membranes was not region specific. Thus 2-OHOA-induced effects on [Ca(2+)](i) transients and cell shortening are likely related to reductions in I(to) function, but PKCalpha translocation does not seem to play a role. The present results indicate that 2-OHOA selectively increases myocyte inotropic responsiveness, which could underlie its beneficial cardiovascular effects.
Borchert
Gudrun H
GH
University of the Balearic Islands, Palma de Mallorca, Spain. gudrunhborchert@compuserve.com
Giggey
Mike
M
Kolar
Frantisek
F
Wong
Tak Ming
TM
Backx
Peter H
PH
Escriba
Pablo V
PV
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006346:Heart Septum / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009829:Oleic Acids / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
C483229:2-hydroxyoleic acid; D002316:Cardiotonic Agents; D009829:Oleic Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015761:4-Aminopyridine; D051571:Protein Kinase C-alpha