|  Help  |  About  |  Contact Us

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

First Author  Axelsson Raja A Year  2022
Journal  Proc Natl Acad Sci U S A Volume  119
Issue  28 Pages  e2204174119
PubMed ID  35787042 Mgi Jnum  J:332420
Mgi Id  MGI:7424783 Doi  10.1073/pnas.2204174119
Citation  Axelsson Raja A, et al. (2022) Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model. Proc Natl Acad Sci U S A 119(28):e2204174119
abstractText  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(+/-) LPAR1(WT), 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.
Quick Links:
 
Quick Links:
 

Expression

Publication --> Expression annotations

 

Other

6 Bio Entities

Trail: Publication

0 Expression