Lysophosphatidic acid induces hypertrophy of neonatal cardiac myocytes via activation of Gi and Rho.
The effect of the lysophospholipid, lysophosphatidic acid (LPA), on signaling and hypertrophy of neonatal rat ventricular cardiomyocytes was examined. Myocytes express mRNA for all three G-protein-coupled LPA receptor subtypes (LPA(1)/Edg-2, LPA(2)/Edg-4, and LPA(3)/Edg-7) as indicated by RT-PCR analysis. LPA inhibits isoproterenol-stimulated cyclic AMP accumulation with an IC(50) approximately 40 nM and promotes phosphorylation of ERK-1/2. LPA also elicits a small, slow onset, and activation of phosphoinositide hydrolysis with EC(50) approximately 400 nM, and stimulates a marked increase in the extent of Rho activation. Longer-term treatment with LPA induces a hypertrophic response in myocytes as indicated by increases in cell size, actin organization, ANF staining of the perinuclear region and activation of ANF promoter-luciferase gene expression. Pretreatment of myocytes with pertussis toxin (PTX) not only blocks the capacity of LPA to inhibit cyclic AMP formation and stimulate ERK phosphorylation, but also inhibits hypertrophic changes in cell morphology and ANF-luciferase gene expression. Neither phospholipase C nor Rho activation is PTX sensitive. The hypertrophic effects of LPA on myocytes are also inhibited by treatment with C3 exoenzyme or by transfection of plasmids expressing either C3 exoenzyme or dominant-negative Rho to block Rho function. Inhibition of ERK activation with PD98059 blocks LPA-induced hypertrophy while inhibitors of phospholipase C (U73122), PKC (GF109203X), or p38MAPK (SB203580) do not. These data suggest that LPA induces cardiomyocyte hypertrophy via a pathway different from the conventional G(q) pathway utilized by phenylephrine, endothelin, and PGF2 alpha and involving activation of a PTX-sensitive G(i)/ERK pathway in conjunction with activation of Rho-mediated signals.
Hilal-Dandan
Randa
R
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA. rdandan@ucsd.edu
Means
Christopher K
CK
Gustafsson
Asa B
AB
Morissette
Michael R
MR
Adams
John W
JW
Brunton
Laurence L
LL
Heller Brown
Joan
J
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008156:Luciferases / Q000378:metabolism; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000473:pathology*; D037342:Pertussis Toxin / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000737:chemistry; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011506:Proteins / Q000737:chemistry; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D010738:Type C Phospholipases / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004963:Estrenes; D005419:Flavonoids; D008246:Lysophospholipids; D010716:Phosphatidylinositols; D011506:Proteins; D011760:Pyrrolidinones; D012333:RNA, Messenger; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D000242:Cyclic AMP; D008156:Luciferases; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010738:Type C Phospholipases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020741:rho GTP-Binding Proteins; D000262:Adenylyl Cyclases; C032881:lysophosphatidic acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one