Specific LPA receptor subtype mediation of LPA‐induced hypertrophy of cardiac myocytes and involvement of Akt and NFκB signal pathways

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-kappaB-luciferase expression. Inhibitors of PI3K (wortmannin), mTOR (rapamycin), and NF-kappaB (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-kappaB and p65 phosphorylation whereas wortmannin showed no effect on NF-kappaB 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-kappaB signaling pathways independently implicate in LPA-stimulated myocardial hypertrophic growth.

Purinergic signaling is required for fluid shear stress-induced NF-κB translocation in osteoblasts

“…LPA also is linked to NF-κB activation in other cellular phenotypes including fibroblasts [38], endothelial cells [39] and cardiac myocytes [40]. LPA signaling increases Ca 2+ i within MC3T3-E1 osteoblastic cells through either receptor LPA 1 or LPA 3 [36].…”

Lysophosphatidic acid (LPA) receptors: Signaling properties and disease relevance

“…In response to cardiac damage, the heart often enlarges to compensate for reduced contractile force, in a process known as hypertrophy. Experiments both in vivo and in vitro showed that LPA 1 and LPA 3 contribute to the hypertrophic response through the activation of G i and multiple downstream effectors, including Rho, PI3K/Akt, and NF-kB [33, 34]. …”

Protective Role for LPA3 in Cardiac Hypertrophy Induced by Myocardial Infarction but Not by Isoproterenol

“…Among the mitogen-activated protein kinases (MAPKs) superfamily, ERK1/2 has been reported to mediate both adaptive (Gαq mediated) (Bueno et al, 2000) and maladaptive (via Gβγ) (Lorenz et al, 2009) processes through different phosphorylation sites within the heart. As the underlying mechanisms of LPA-induced cardiomyocyte hypertrophy involve activation of Akt and ERK-NFκB (Chen et al, 2008; Yang et al, 2013b), with Gαq-dependent signaling by LPA 3 reported in other cell systems like vascular smooth muscle (Kim et al, 2006), we speculate that in contrast with detrimental effects of ISO-β-AR activation, LPA-LPA 3 signaling might represent another upstream stimulus for adaptive hypertrophy.…”

“…LPA induces cardiomyocyte hypertrophy through a mechanism involving both Gi and the small G protein Rho (Hilal-Dandan et al, 2004), which is different from G proteins that ISO-β-AR couples to. After binding to Gi, LPA 3 activates Akt and ERK-NFκB, and then promotes the expression of fetal phenotype gene markers ANP and BNP (Chen et al, 2008; Yang et al, 2013b). These data suggest that β-AR and LPA 3 mediate distinct effectors and, in support of this, the present study provides experimental evidence for LPA-LPA 3 signaling being distinct from ISO-β-AR-mediated myocardial hypertrophy.…”

“…Our previous study found that cardiomyocyte hypertrophy could be induced by LPA, via Akt and ERK-NFκB signaling pathways (Chen et al, 2008). Moreover, we have recently identified pro-hypertrophic effects of LPA on neonatal rat cardiomyocytes (NRCMs) are mediated through the LPA 3 receptor (encoded by Lpar3 ) (Yang et al, 2013b).…”