Modulation of myocardial contractility by lysophosphatidic acid (LPA).
Lysophosphatidic acid (LPA) is a phospholipid messenger, which is released from activated platelets and leukocytes. This study examined the effects of LPA on myocardial contractility and characterized the signal transduction pathway involved in these effects. Functional effects of LPA were determined in isolated, electrically driven human myocardial preparations and rat cardiac myocytes. In human atrial and ventricular myocardial preparations, LPA (100 micromol/l) decreased isoprenaline (0.03 micromol/l) enhanced force of contraction by 17 +/- 2% and 28 +/- 3%, respectively. The effect of LPA was attenuated by suramin (1 mmol/l). In isolated rat cardiomyocytes, LPA (1-100 micromol/l) concentration dependently abolished isoprenaline (0.03 micromol/l) induced increase in cell shortening. This antiadrenergic effect was blunted after pretreatment with pertussis toxin (5 microg/ml, 12 h). Forskolin (10 micromol/l) stimulated adenylyl cyclase activity was inhibited by LPA in human myocardial membranes. PCR analysis of human atrial and ventricular cDNAs revealed the expression of two cognate LPA receptors: EDG-2 and EDG-7. Our results suggest that LPA exerts antiadrenergic effects on force of contraction in human and rodent myocardium via a Galpha(i/o) protein-mediated mechanism, most probably by LPA binding to the mammalian LPA receptors EDG-2 and/or EDG-7. This newly discovered action of LPA might be of pathophysiological importance in conditions like myocardial ischemia or inflammatory disorders when LPA release is enhanced.
Cremers
Bodo
B
Medizinische Klinik und Poliklinik, Innere Medizin III,Universitätskliniken des Saarlandes, 66421, Homburg, Germany. cremers@med-in.uni-sb.de
Flesch
Markus
M
Kostenis
Evi
E
Maack
Christoph
C
Niedernberg
Anke
A
Stoff
Alexander
A
Südkamp
Michael
M
Wendler
Olaf
O
Böhm
Michael
M
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013498:Suramin / Q000494:pharmacology
D008246:Lysophospholipids; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013498:Suramin; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases