Lysophosphatidic Acid Induces ECM Production via Activation of the Mechanosensitive YAP/TAZ Transcriptional Pathway in Trabecular Meshwork Cells

Abstract

PurposeLysophosphatidic acid (LPA), a bioactive lipid, has been shown to increase resistance to aqueous humor outflow (AH) through the trabecular meshwork (TM). The molecular basis for this response of the TM to LPA, however, is not completely understood. In this study, we explored the possible involvement of mechanosensitive Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding domain (TAZ), transcriptional activation in extracellular matrix (ECM) production by LPA-induced contractile activity in human TM cells (HTM).MethodsThe responsiveness of genes encoding LPA receptors (LPARs), LPA hydrolyzing lipid phosphate phosphatases (LPPs), and the LPA-generating autotaxin (ATX) to cyclic mechanical stretch in HTM cells, was evaluated by RT-quantitative (q)PCR. The effects of LPA and LPA receptor antagonists on actomyosin contractile activity, activation of YAP/TAZ, and levels of connective tissue growth factor (CTGF), and Cyr61 and ECM proteins in HTM cells were determined by immunoblotting, mass spectrometry, and immunofluorescence analyses.ResultsCyclic mechanical stretch significantly increased the expression of several types of LPARs, LPP1, and ATX in HTM cells. LPA and LPA receptor–dependent contractile activity led to increases in both, the protein levels and activation of YAP/TAZ, and increased the levels of CTGF, Cyr61, α-smooth muscle actin (α–SMA), and ECM proteins in HTM cells.ConclusionsThe results of this study reveal that LPA and its receptors stimulate YAP/TAZ transcriptional activity in HTM cells by modulating cellular contractile tension, and augment expression of CTGF that in turn leads to increased production of ECM. Therefore, YAP/TAZ-induced increases in CTGF and ECM production could be an important molecular mechanism underlying LPA-induced resistance to AH outflow and ocular hypertension.

Alteration in Lysophospholipids and Converting Enzymes in Glaucomatous Optic Nerves

“…Our findings are inconsistent with aberration in the LPA-ATX pathway in the glaucomatous ON, unlike that observed in the anterior eye chamber/trabecular meshwork. 44,45,[49][50][51] Aside from the ATX-LPA pathway, there are numerous metabolic mechanisms that are responsible for the synthesis and breakdown of LPLs. We evaluated several pathways that interconnect the metabolism of LPA, LPE, and LPC ( Supplementary Fig.…”

YAP nuclear‐cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism

“…Furthermore, PA can directly interact with the Hippo signaling pathway components LATS and NF2 to disrupt LATS‐MOB1 complex formation and NF2‐mediated LATS membrane translocation and activation, respectively, resulting in inhibition of LATS kinase activity and upregulation of the nuclear activity of the transcriptional regulator YAP (Han et al, 2018). Lysophosphatidic acid (LPA), which is the smallest and simplest phospholipid, as well as a key precursor in the early stages of eukaryotic phospholipid biosynthesis, has been found to stimulate YAP/TAZ transcriptional activity in HTM cells by regulating cell contraction and increasing CTGF expression, which, in turn, leads to an increase in ECM production (Park et al, 2016; Ho et al, 2018). Furthermore, YAP/TAZ activity can be regulated by serum‐derived sphingosine‐1‐phosphate (S1P), LPA, GPCR signals, and the actin‐myosin cytoskeleton.…”

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

“…Currently, a novel study focused on the function of seRNA UCA1-activated YAP, and discovered that aberrant activation of YAP/TAZ (transcriptional coactivator with PDZ-binding domain) axis exists in the microenvironment of various cancers including GC, CRC, lung cancer and breast cancer [94]. YAP/TAZ activation remarkably increases contractile activity and upregulates connective tissue growth factor (CTGF) and Cyr61, which promotes α-SMA overexpression and ECM proteins deposition including laminin, collagen type I and fibronectin [126]. Of critical note, SE-boosted seRNA might drive cancer-associated fibroblasts (CAFs) proliferation and myofibroblast differentiation [96].…”