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

Publication ,  Journal Article
Ho, LTY; Skiba, N; Ullmer, C; Rao, PV
Published in: Invest Ophthalmol Vis Sci
April 1, 2018

PURPOSE: Lysophosphatidic 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). METHODS: The 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. RESULTS: Cyclic 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. CONCLUSIONS: The 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.

Duke Scholars

Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

April 1, 2018

Volume

59

Issue

5

Start / End Page

1969 / 1984

Location

United States

Related Subject Headings

  • Young Adult
  • YAP-Signaling Proteins
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Transcription Factors
  • Trans-Activators
  • Trabecular Meshwork
  • Tissue Donors
  • Receptors, Lysophosphatidic Acid
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
 

Citation

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MLA
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Ho, L. T. Y., Skiba, N., Ullmer, C., & Rao, P. V. (2018). Lysophosphatidic Acid Induces ECM Production via Activation of the Mechanosensitive YAP/TAZ Transcriptional Pathway in Trabecular Meshwork Cells. Invest Ophthalmol Vis Sci, 59(5), 1969–1984. https://doi.org/10.1167/iovs.17-23702
Ho, Leona T. Y., Nikolai Skiba, Christoph Ullmer, and Ponugoti Vasantha Rao. “Lysophosphatidic Acid Induces ECM Production via Activation of the Mechanosensitive YAP/TAZ Transcriptional Pathway in Trabecular Meshwork Cells.Invest Ophthalmol Vis Sci 59, no. 5 (April 1, 2018): 1969–84. https://doi.org/10.1167/iovs.17-23702.
Ho, Leona T. Y., et al. “Lysophosphatidic Acid Induces ECM Production via Activation of the Mechanosensitive YAP/TAZ Transcriptional Pathway in Trabecular Meshwork Cells.Invest Ophthalmol Vis Sci, vol. 59, no. 5, Apr. 2018, pp. 1969–84. Pubmed, doi:10.1167/iovs.17-23702.

Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

April 1, 2018

Volume

59

Issue

5

Start / End Page

1969 / 1984

Location

United States

Related Subject Headings

  • Young Adult
  • YAP-Signaling Proteins
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Transcription Factors
  • Trans-Activators
  • Trabecular Meshwork
  • Tissue Donors
  • Receptors, Lysophosphatidic Acid
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger