Lysophosphatidic acid induces hypertrophy of neonatal cardiac myocytes via activation of Gi and Rho

Autor: John W. Adams, Joan Heller Brown, Michael R. Morissette, Randa Hilal-Dandan, Åsa B. Gustafsson, Laurence L. Brunton, Christopher K. Means
Rok vydání: 2004
Předmět:
rho GTP-Binding Proteins
MAPK/ERK pathway
Time Factors
GTP-Binding Protein alpha Subunits
Gi-Go
Phosphatidylinositols
Rats
Sprague-Dawley
Adenylyl cyclase
chemistry.chemical_compound
Lysophosphatidic acid
Cyclic AMP
Myocyte
Myocytes
Cardiac
Enzyme Inhibitors
Estrenes
Luciferases
Protein Kinase C
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Reverse Transcriptase Polymerase Chain Reaction
Hydrolysis
Pyrrolidinones
Cell biology
Phosphorylation
lipids (amino acids
peptides
and proteins)
biological phenomena
cell phenomena
and immunity
Cardiology and Cardiovascular Medicine
Adenylyl Cyclases
medicine.medical_specialty
Blotting
Western
Biology
Transfection
Pertussis toxin
Models
Biological
Inhibitory Concentration 50
Internal medicine
medicine
Animals
RNA
Messenger
Molecular Biology
Protein kinase C
Flavonoids
Dose-Response Relationship
Drug
Phospholipase C
Proteins
Rats
Enzyme Activation
Endocrinology
Animals
Newborn
Microscopy
Fluorescence
Pertussis Toxin
chemistry
Protein Biosynthesis
Type C Phospholipases
GTP-Binding Protein alpha Subunits
Gq-G11
Lysophospholipids
Zdroj: Journal of Molecular and Cellular Cardiology. 36:481-493
ISSN: 0022-2828
Popis: 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.
Databáze: OpenAIRE
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