Dataset Information

Endogenous lysophosphatidic acid (LPA₁ ) receptor agonists demonstrate ligand bias between calcium and ERK signalling pathways in human lung fibroblasts.

ABSTRACT:

Background and purpose

Human lung fibroblasts (HLF) express high levels of the LPA₁ receptor, a GPCR that responds to the endogenous lipid mediator, lysophosphatidic acid (LPA). Several molecular species or analogues of LPA exist and have been detected in biological fluids such as serum and plasma. The most widely expressed of the LPA receptor family is the LPA₁ receptor, which predominantly couples to G_q/11 , G_i/o and G_12/13 proteins. This promiscuity of coupling raises the possibility that some of the LPA analogues may bias the LPA₁ receptor towards one signalling pathway over another.

Experimental approach

Here, we have explored the signalling profiles of a range of LPA analogues in HLF that endogenously express the LPA₁ receptor. HLF were treated with LPA analogues and receptor activation monitored via calcium mobilization and ERK phosphorylation.

Key results

These analyses demonstrated that the 16:0, 17:0, 18:2 and C18:1 LPA analogues appear to exhibit ligand bias between ERK phosphorylation and calcium mobilization when compared with 18:1 LPA, one of the most abundant forms of LPA that has been found in human plasma.

Conclusion and implications

The importance of LPA as a key signalling molecule is shown by its widespread occurrence in biological fluids and its association with disease conditions such as fibrosis and cancer. These findings have important, as yet unexplored, implications for the (patho-) physiological signalling of the LPA₁ receptor, as it may be influenced not only by the concentration of endogenous ligand but the isoform as well.

SUBMITTER: Sattikar A

PROVIDER: S-EPMC5241385 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

Endogenous lysophosphatidic acid (LPA1 ) receptor agonists demonstrate ligand bias between calcium and ERK signalling pathways in human lung fibroblasts.

Sattikar Afrah A Dowling Mark R MR Rosethorne Elizabeth M EM

British journal of pharmacology 20170106 3

<h4>Background and purpose</h4>Human lung fibroblasts (HLF) express high levels of the LPA1 receptor, a GPCR that responds to the endogenous lipid mediator, lysophosphatidic acid (LPA). Several molecular species or analogues of LPA exist and have been detected in biological fluids such as serum and plasma. The most widely expressed of the LPA receptor family is the LPA1 receptor, which predominantly couples to Gq/11 , Gi/o and G12/13 protein ...[more]

PMID: 27864940

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Project description:Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA1 and LPA3 is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA1 and LPA3 in the heart is unknown. Methods and Results: By using LPA3 and LPA1 knockout mice, and neonatal SD rats treated with Ki16425 (LPA1/LPA3 inhibitor), we found that the number of proliferating cardiomyocytes, detected by coimmunostaining pH3, Ki67 or BrdU with cardiac troponin T, was significantly decreased in the LPA3 knockout mice and the Ki16425-treated rats but not in the LPA1 knockout mice during the first week of postnatal life. Using a myocardial infarction (MI) model, we found that cardiac function and the number of proliferating cardiomyocytes were decreased in the neonatal LPA3 KO mice and increased in the AAV9-mediated cardiac-specific LPA3 overexpression mice. By using lineage tracing and AAV9-LPA3, we further found that LPA3 overexpression in adult mice enhances cardiac function and heart regeneration as assessed by pH3-, Ki67-, and Aurora B-positive cardiomyocytes and clonal cardiomyocytes after MI. Genome-wide transcriptional profiling and additional mechanistic studies showed that LPA induces cardiomyocyte proliferation through the PI3K/AKT, BMP-Smad1/5, Hippo/YAP and MAPK/ERK pathways in vitro, whereas only ERK was confirmed to be activated by LPA-LPA3 signaling in vivo. Conclusion: Our study reports that LPA3-mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA3 overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA3 potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI.