Specific LPA receptor subtype mediation of LPA‐induced hypertrophy of cardiac myocytes and involvement of Akt and NFκB signal pathways
- 21 September 2007
- journal article
- research article
- Published by Wiley in Journal of Cellular Biochemistry
- Vol. 103 (6), 1718-1731
- https://doi.org/10.1002/jcb.21564
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid with diverse functions mediated via G-protein-coupled receptors (GPCRs). In view of the elevated levels of LPA in acute myocardial infarction (MI) patients we have conducted studies aimed at identifying specific LPA receptor subtypes and signaling events that may mediate its actions in hypertrophic remodeling. Experiments were carried out in cultured neonatal rat cardiomyocytes (NRCMs) exposed to LPA and in a rat MI model. In NRCMs, LPA-induced hypertrophic growth was completely abrogated by DGPP, an LPA1/LPA3 antagonist. The LPA3 agonist OMPT, but not the LPA2 agonist dodecylphosphate, promoted hypertrophy as examined by 3[H]-Leucine incorporation, ANF-luciferase expression and cell area. In in vivo experiments, LPA1, LPA2 and LPA3 mRNA levels as well as LPA1 and LPA3 protein levels increased together with left ventricular remodeling (LVRM) after MI. In addition, LPA stimulated the phosphorylation of Akt and p65 protein and activated NF-κB-luciferase expression. Inhibitors of PI3K (wortmannin), mTOR (rapamycin), and NF-κB (PDTC or SN50) effectively prevented LPA-induced 3[H]-Leucine incorporation and ANF-luciferase expression. Furthermore, ERK inhibitors (U0126 and PD98059) suppressed LPA-stimulated activation of NF-κB and p65 phosphorylation whereas wortmannin showed no effect on NF-κB activation. Our findings indicate that LPA3 and/or LPA1 mediate LPA-induced hypertrophy of NRCMs and that LPA1 and LPA3 may be involved in LVRM of MI rats. Moreover, Akt and NF-κB signaling pathways independently implicate in LPA-stimulated myocardial hypertrophic growth. J. Cell. Biochem. 103: 1718–1731, 2008.Keywords
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