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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\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ) with\n                    <jats:italic>Lpar1<\/jats:italic>\n                    -ablated mice to create mice carrying both genetic changes (403\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    LPAR1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) and assessed development of cardiac hypertrophy and fibrosis. Compared with 403\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    LPAR1\n                    <jats:sup>WT<\/jats:sup>\n                    , 403\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    LPAR1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice developed significantly less hypertrophy and fibrosis. Single-nucleus RNA sequencing of left ventricular tissue demonstrated that\n                    <jats:italic>Lpar1<\/jats:italic>\n                    was predominantly expressed by lymphatic endothelial cells (LECs) and cardiac fibroblasts.\n                    <jats:italic>Lpar1<\/jats:italic>\n                    ablation reduced the population of LECs, confirmed by immunofluorescence staining of the LEC markers Lyve1 and Ccl21a and, by in situ hybridization, for\n                    <jats:italic>Reln<\/jats:italic>\n                    and\n                    <jats:italic>Ccl21a<\/jats:italic>\n                    .\n                    <jats:italic>Lpar1<\/jats:italic>\n                    ablation also altered the distribution of fibroblast cell states. FB1 and FB2 fibroblasts decreased while FB0 and FB3 fibroblasts increased. Our findings indicate that\n                    <jats:italic>Lpar1<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2204174119","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T14:57:18Z","timestamp":1657033038000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":24,"title":["Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model"],"prefix":"10.1073","volume":"119","author":[{"given":"Anna","family":"Axelsson Raja","sequence":"first","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Cardiology, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Wakimoto","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical 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