{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T19:16:29Z","timestamp":1774466189057,"version":"3.50.1"},"reference-count":73,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,4]]},"abstract":"\n BACKGROUND:<\/jats:title>\n Impaired angiogenesis underpins cardiovascular disease, particularly in people with diabetes; however, molecular mechanisms are still poorly understood. This study aims to decipher the role of an emerging antiangiogenic protein, FKBPL (FK506-binding protein\u2013like), on cardiac structure and function, vascular integrity, and inflammatory signaling in in vivo and in vitro models of diabetes.<\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n In vivo, FKBPL transgenic mice (\n fkbpl<\/jats:italic>\n \n \n +\/\u2212<\/jats:italic>\n <\/jats:bold>\n <\/jats:sup>\n ) were used to examine the metabolic and cardiovascular function and FKBPL-mediated mechanisms in streptozotocin-induced diabetes. In addition, comprehensive in vitro assessments of endothelial function and mechanisms were performed in normal\/high-glucose and high\/low-FKBPL conditions.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n Fkbpl<\/jats:italic>\n \n \n +\/\u2212<\/jats:italic>\n <\/jats:bold>\n <\/jats:sup>\n mice show signs of early cardiac remodeling (increased E\/A [early-to-atrial filling velocity ratio] ratio,\n P<\/jats:italic>\n =0.047, and cardiomyocytes size,\n P<\/jats:italic>\n =0.0018; reduced collagen deposition,\n P<\/jats:italic>\n =0.013;\n col1a1<\/jats:italic>\n mRNA reduction,\n P<\/jats:italic>\n =0.0028) and aberrant expression of cardiac vascular dysfunction proteins (ICAM-1 [intercellular adhesion molecule 1],\n P<\/jats:italic>\n <0.001, SIRT-1 [sirtuin 1];\n P<\/jats:italic>\n <0.001). Proinflammatory cardiac profile was prominent in\n fkbpl<\/jats:italic>\n \n \n +\/\u2212<\/jats:italic>\n <\/jats:bold>\n <\/jats:sup>\n murine hearts with increased protein expression of ICAM-1, IL (interleukin)-12p40, IL-15, IL-22, LIF (leukemia inhibitory factor), lipocalin-2, MMP (matrix metalloproteinase)-3\/-9, periostin, serpin E1, and VCAM-1 (vascular cell adhesion molecule 1), which were decreased in diabetes. In diabetic mice with low FKBPL expression, glucose metabolism deteriorated, whereas vascular dysfunction improved. In normal glucose conditions, FKBPL knockdown in human aortic endothelial cells reduced VE-cadherin (vascular endothelial cadherin;\n P<\/jats:italic>\n =0.0016) and impaired endothelial barrier (\n P<\/jats:italic>\n <0.001). In high-glucose conditions, endothelial FKBPL knockdown improved angiogenesis, however overexpression of FKBPL reduced angiogenesis by inhibiting the FGF (fibroblast growth factor) and PDGF (platelet-derived growth factor) pathways (\n P<\/jats:italic>\n <0.001) and increasing proinflammatory pathways (TGF [transforming growth factor]-\u03b2,\n P<\/jats:italic>\n <0.001; leukocyte migration,\n P<\/jats:italic>\n =0.033; IL-7 signaling,\n P<\/jats:italic>\n =0.039), by upregulating microRNA (miR)-29b-3p (\n P<\/jats:italic>\n =0.01) and miR-302b-5p (\n P<\/jats:italic>\n =0.03), likely via CD44 (cluster of differentiation). FKBPL-based peptide mimetic, AD-01 (1 nM), in high-glucose conditions, upregulated endothelial\n vcam1<\/jats:italic>\n and\n glut1<\/jats:italic>\n mRNA expression, independent of miR-302b-5p.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n FKBPL plays an important role in glucose metabolism, endothelial function, angiogenesis, cardiac inflammation and function, and could be explored as a therapeutic target of cardiovascular disease both in nondiabetes and diabetes settings using precision medicine approach.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/atvbaha.125.323053","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T10:00:12Z","timestamp":1770890412000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic Loss of FKBPL Uncovers Diabetes-Dependent Pathways of Myocardial and Vascular Injury"],"prefix":"10.1161","volume":"46","author":[{"given":"Abdelrahim","family":"Alqudah","sequence":"first","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine (A.A., K.S.E., K.M.O., R.M., G.H.L.-C., D.J.G., L.M.), Queen\u2019s University Belfast, Northern Ireland, United Kingdom."},{"name":"Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan (A.A.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-0104","authenticated-orcid":true,"given":"Kevin S.","family":"Edgar","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine (A.A., K.S.E., K.M.O., R.M., G.H.L.-C., D.J.G., L.M.), Queen\u2019s University Belfast, Northern Ireland, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karla M.","family":"O'Neill","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine (A.A., K.S.E., K.M.O., R.M., G.H.L.-C., D.J.G., L.M.), Queen\u2019s University Belfast, Northern Ireland, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9244-8683","authenticated-orcid":true,"given":"Ross","family":"McNally","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine (A.A., K.S.E., K.M.O., R.M., G.H.L.-C., D.J.G., L.M.), Queen\u2019s University Belfast, Northern Ireland, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sareh","family":"Zhand","sequence":"additional","affiliation":[{"name":"School of Life Sciences & Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, New South Wales, Australia (S.Z., M.C., L.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3717-4722","authenticated-orcid":true,"given":"Natalie","family":"Le","sequence":"additional","affiliation":[{"name":"Heart Research Institute, The University of Sydney, New South Wales, Australia (N.L., M.M.K.)."},{"name":"Centre for Peripheral Artery Disease, Heart Research Institute, Sydney, New South Wales, Australia (N.L., M.M.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4010-5248","authenticated-orcid":true,"given":"Michael","family":"Chhor","sequence":"additional","affiliation":[{"name":"School of Life Sciences & Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, New South Wales, Australia (S.Z., M.C., L.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Short","sequence":"additional","affiliation":[{"name":"School of Pharmacy (A.S., T.R.), Queen\u2019s University Belfast, Northern Ireland, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7353-0932","authenticated-orcid":true,"given":"Mary M.","family":"Kavurma","sequence":"additional","affiliation":[{"name":"Heart Research Institute, The University of Sydney, New South Wales, Australia (N.L., M.M.K.)."},{"name":"Centre for Peripheral Artery Disease, Heart Research Institute, Sydney, New South Wales, Australia (N.L., M.M.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillermo H.","family":"Lopez-Campos","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine (A.A., K.S.E., K.M.O., R.M., G.H.L.-C., D.J.G., L.M.), Queen\u2019s University Belfast, Northern Ireland, United 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