{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:55:18Z","timestamp":1792702518750,"version":"4.5.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Despite its established significance in fibrotic cardiac remodeling, clinical benefits of global inhibition of TGF (transforming growth factor)-\u03b21 signaling remain controversial. LRG1 (leucine-rich-\u03b12 glycoprotein 1) is known to regulate endothelial TGF\u03b2 signaling. This study evaluated the role of LRG1 in cardiac fibrosis and its transcriptional regulatory network in cardiac fibroblasts.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Pressure overload\u2013induced heart failure was established by transverse aortic constriction. Western blot, quantitative reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to evaluate the expression level and pattern of interested targets or pathology during fibrotic cardiac remodeling. Cardiac function was assessed by pressure-volume loop analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              LRG1 expression was significantly suppressed in left ventricle of mice with transverse aortic constriction\u2013induced fibrotic cardiac remodeling (mean difference, \u22120.00085 [95% CI, \u22120.0013 to \u22120.00043];\n              <jats:italic>P<\/jats:italic>\n              =0.005) and of patients with end-stage ischemic-dilated cardiomyopathy (mean difference, 0.13 [95% CI, 0.012\u20130.25];\n              <jats:italic>P<\/jats:italic>\n              =0.032). More profound cardiac fibrosis (mean difference, \u22120.014% [95% CI, \u22120.029% to \u22120.00012%];\n              <jats:italic>P<\/jats:italic>\n              =0.048 for interstitial fibrosis; mean difference, \u22121.3 [95% CI, \u22122.5 to \u22120.2];\n              <jats:italic>P<\/jats:italic>\n              =0.016 for perivascular fibrosis), worse cardiac dysfunction (mean difference, \u22122.5 ms [95% CI, \u22124.5 to \u22120.4 ms];\n              <jats:italic>P<\/jats:italic>\n              =0.016 for Tau-g; mean difference, 13% [95% CI, 2%\u201324%];\n              <jats:italic>P<\/jats:italic>\n              =0.016 for ejection fraction), and hyperactive TGF\u03b2 signaling in transverse aortic constriction\u2013operated\n              <jats:italic>Lrg1<\/jats:italic>\n              -deficient mice (mean difference, \u22120.27 [95% CI, \u22120.47 to \u22120.07];\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001), which could be reversed by cardiac-specific\n              <jats:italic>Lrg1<\/jats:italic>\n              delivery mediated by adeno-associated virus 9. Mechanistically, LRG1 inhibits cardiac fibroblast activation by competing with TGF\u03b21 for receptor binding, while PPAR (peroxisome proliferator-activated receptor)-\u03b2\/\u03b4 and TGF\u03b21 collaboratively regulate\n              <jats:italic>LRG1<\/jats:italic>\n              expression via SMRT (silencing mediator for retinoid and thyroid hormone receptor). We further demonstrated functional interactions between LRG1 and PPAR\u03b2\/\u03b4 in cardiac fibroblast activation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our results established a highly complex molecular network involving LRG1, TGF\u03b21, PPAR\u03b2\/\u03b4, and SMRT in regulating cardiac fibroblast activation and cardiac fibrosis. Targeting LRG1 or PPAR\u03b2\/\u03b4 represents a promising strategy to control pathological cardiac remodeling in response to chronic pressure overload.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.119.005962","type":"journal-article","created":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T10:00:26Z","timestamp":1576231226000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":45,"title":["Collaborative Regulation of LRG1 by TGF-\u03b21 and PPAR-\u03b2\/\u03b4 Modulates Chronic Pressure Overload\u2013Induced Cardiac Fibrosis"],"prefix":"10.1161","volume":"12","author":[{"given":"Chenghao","family":"Liu","sequence":"first","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok Ting","family":"Lim","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Hui Yen","family":"Teo","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle Si Ying","family":"Tan","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhura Dattatraya","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beiying","family":"Qiu","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology, Proteos, Agency for Science, Technology and Research, Singapore (B.Q., N.S.T., W.H., X.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Li","sequence":"additional","affiliation":[{"name":"Anatomy and Histology, School of Medical Sciences, Bosch Institute, University of Sydney, Australia (A.L., S.L., C.G.d.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Lal","sequence":"additional","affiliation":[{"name":"Anatomy and Histology, School of Medical Sciences, Bosch Institute, University of Sydney, Australia (A.L., S.L., C.G.d.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristobal G.","family":"dos Remedios","sequence":"additional","affiliation":[{"name":"Anatomy and Histology, School of Medical Sciences, Bosch Institute, University of Sydney, Australia (A.L., S.L., C.G.d.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguan Soon","family":"Tan","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."},{"name":"School of Biological Sciences (N.S.T.), Nanyang Technological University Singapore."},{"name":"Institute of Molecular and Cell Biology, Proteos, Agency for Science, Technology and Research, Singapore (B.Q., N.S.T., W.H., X.W.)."},{"name":"KK Research Centre, KK Women\u2019s and Children Hospital, Singapore (N.S.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Wahli","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."},{"name":"INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse, France (W.W.)."},{"name":"Centre for Integrative Genomics, University of Lausanne, Le Genopode, Switzerland (W.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Alan","family":"Ferenczi","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Song","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine (C.L., S.T.L., M.H.Y.T., M.S.Y.T., M.D.K., N.S.T., W.W., M.A.F., W.S., X.W.), Nanyang Technological University Singapore."},{"name":"National Heart Centre Singapore 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