Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model

Anna Axelsson Raja, Hiroko Wakimoto, Daniel M DeLaughter, Daniel Reichart, Joshua Gorham, David A Conner, Mingyue Lun, Clemens K Probst, Norihiko Sakai, Rachel S Knipe, Sydney B Montesi, Barry Shea, Leonard P Adam, Leslie A Leinwand, William Wan, Esther Sue Choi, Eric L Lindberg, Giannino Patone, Michela Noseda, Norbert HübnerChristine E Seidman, Andrew M Tager, J G Seidman*, Carolyn Y Ho

*Corresponding author for this work

Abstract

Myocardial fibrosis is a key pathologic feature of hypertrophic cardiomyopathy (HCM). However, the fibrotic pathways activated by HCM-causing sarcomere protein gene mutations are poorly defined. Because lysophosphatidic acid is a mediator of fibrosis in multiple organs and diseases, we tested the role of the lysophosphatidic acid pathway in HCM. Lysphosphatidic acid receptor 1 (LPAR1), a cell surface receptor, is required for lysophosphatidic acid mediation of fibrosis. We bred HCM mice carrying a pathogenic myosin heavy-chain variant (403+/-) with Lpar1-ablated mice to create mice carrying both genetic changes (403+/- LPAR1 -/-) and assessed development of cardiac hypertrophy and fibrosis. Compared with 403+/- LPAR1WT, 403+/- LPAR1 -/- mice developed significantly less hypertrophy and fibrosis. Single-nucleus RNA sequencing of left ventricular tissue demonstrated that Lpar1 was predominantly expressed by lymphatic endothelial cells (LECs) and cardiac fibroblasts. Lpar1 ablation reduced the population of LECs, confirmed by immunofluorescence staining of the LEC markers Lyve1 and Ccl21a and, by in situ hybridization, for Reln and Ccl21a. Lpar1 ablation also altered the distribution of fibroblast cell states. FB1 and FB2 fibroblasts decreased while FB0 and FB3 fibroblasts increased. Our findings indicate that Lpar1 is expressed predominantly by LECs and fibroblasts in the heart and is required for development of hypertrophy and fibrosis in an HCM mouse model. LPAR1 antagonism, including agents in clinical trials for other fibrotic diseases, may be beneficial for HCM.

Original languageEnglish
Article numbere2204174119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number28
Pages (from-to)e2204174119
ISSN0027-8424
DOIs
Publication statusPublished - 12 Jul 2022

Keywords

  • Animals
  • Cardiomyopathy, Hypertrophic/genetics
  • Carrier Proteins
  • Disease Models, Animal
  • Endothelial Cells/pathology
  • Fibrosis
  • Hypertrophy/pathology
  • Mice
  • Receptors, Lysophosphatidic Acid/genetics

Fingerprint

Dive into the research topics of 'Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model'. Together they form a unique fingerprint.

Cite this