{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:53:46Z","timestamp":1787018026754,"version":"build-2736575974"},"reference-count":73,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Monocyte-derived macrophages play a significant role in the initiation and progression of atherosclerosis by transforming into lipid-laden foam cells and regulating vascular inflammation. However, the molecular mechanisms that regulate macrophage lipid accumulation, phenotype, efferocytic capacity, and atherosclerosis are incompletely understood. Our preliminary studies revealed increased expression of LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4) in human atherosclerotic arteries. Additional experiments demonstrated increased LGR4 levels in atherogenic oxidized low-density lipoprotein\u2013treated macrophages. However, the macrophage-specific role of LGR4 in atherogenesis has never been investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      To investigate the role of myeloid cell Lgr4 in atherosclerosis development, myeloid cell-specific\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      knockout (\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      <jats:sup>f\/f<\/jats:sup>\n                      <jats:italic toggle=\"yes\">LysM<\/jats:italic>\n                      Cre\n                      <jats:sup>+\/-<\/jats:sup>\n                      ,\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      <jats:sup>\u0394M<\/jats:sup>\n                      ) and littermate control\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      <jats:sup>f\/f<\/jats:sup>\n                      (\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      <jats:sup>WT<\/jats:sup>\n                      ) mice were injected intraperitoneally with adeno-associated viral vector (serotype 8) for h\n                      <jats:italic toggle=\"yes\">PCSK9<\/jats:italic>\n                      and fed a Western diet for 16 weeks. Various in vitro cell-based assays, molecular biology techniques, and immunohistological approaches were used to evaluate the functional roles of macrophage Lgr4 and underlying signaling mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Oil red O staining of whole aortas and aortic root sections demonstrated reduced atherosclerosis in\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      <jats:sup>\u0394M<\/jats:sup>\n                      mice compared with sex-matched\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      <jats:sup>WT<\/jats:sup>\n                      mice. However, no changes in circulating monocyte frequencies were detected. Histochemical staining performed on aortic root sections revealed smaller necrotic cores and higher collagen content in\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      <jats:sup>\u0394M<\/jats:sup>\n                      mice. Additionally,\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      <jats:sup>\u0394M<\/jats:sup>\n                      mice exhibited lower fat mass and blood glucose levels, while plasma total cholesterol was comparable to that of control mice. Further in vitro and ex vivo studies demonstrated reduced lipid accumulation, enhanced efferocytic capacity, a suppressed proinflammatory phenotype, and attenuated expression of different low-density lipoprotein uptake genes in\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      -deficient macrophages. Moreover,\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      knockout macrophages displayed increased cholesterol efflux capacity and reduced activation of oxidized low-density lipoprotein\u2013induced Wnt (Wingless-related integration site)\/\u03b2-catenin signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      These findings suggest that myeloid cell\n                      <jats:italic toggle=\"yes\">Lgr4<\/jats:italic>\n                      contributes to atherosclerotic lesion formation via stimulating macrophage lipid accumulation, impairing efferocytic capacity, and promoting a proinflammatory phenotype. Collectively, these results identify macrophage LGR4 as a novel therapeutic target for atherosclerosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.324159","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T09:01:40Z","timestamp":1782982900000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Myeloid Cell-Specific Deletion of LGR4 Suppresses Atherosclerotic Lesion Formation"],"prefix":"10.1161","volume":"46","author":[{"given":"Ishita","family":"Kathuria","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy (I.K., R.V.A., M.A.A.M., N.P., M.O.-B., U.P.S., M.A.G., B.S.), The University of Tennessee Health Science Center, Memphis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1724-4218","authenticated-orcid":true,"given":"Ravi Varma","family":"Aithabathula","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy (I.K., R.V.A., M.A.A.M., N.P., M.O.-B., U.P.S., M.A.G., B.S.), The University of Tennessee Health Science Center, Memphis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. Abdullah","family":"Al Mamun","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy (I.K., R.V.A., M.A.A.M., N.P., M.O.-B., U.P.S., M.A.G., B.S.), The University of Tennessee Health Science Center, Memphis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5848-8673","authenticated-orcid":true,"given":"Naveed","family":"Pervaiz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy (I.K., R.V.A., M.A.A.M., N.P., M.O.-B., U.P.S., M.A.G., B.S.), The University of Tennessee Health Science Center, Memphis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indira","family":"Neeli","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Biochemistry, College of Medicine (I.N.), The University of Tennessee Health Science Center, 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