{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:40:15Z","timestamp":1784310015017,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL093215"],"award-info":[{"award-number":["HL093215"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL132908"],"award-info":[{"award-number":["HL132908"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK103616"],"award-info":[{"award-number":["DK103616"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"George and Mary Thompson Fellowship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Reduced levels of the sensory nerve neuropeptide substance P (SP) have been reported in the diabetic rat heart, the consequence being a loss of cardioprotection in response to ischemic post-conditioning. We considered whether this loss of SP also predisposes the heart to non-ischemic diabetic cardiomyopathy in the form of fibrosis and hypertrophy. We report that diabetic Leprdb\/db mice have reduced serum SP and that administration of exogenous replacement SP ameliorated cardiac fibrosis. Cardiac hypertrophy did not occur in Leprdb\/db mice. Cardiac fibroblasts exposed to high glucose converted to a myofibroblast phenotype and produced excess extracellular matrix proteins; this was prevented by the presence of SP in the culture media. Cardiac fibroblasts exposed to high glucose produced increased amounts of the receptor for advanced glycation end products, reactive oxygen species and inflammatory cytokines, all of which were prevented by SP. Cultured macrophages assumed an M1 pro-inflammatory phenotype in response to high glucose as indicated by increased TNF-\u03b1, CCL2, and IL-6. SP promoted a shift to the reparative M2 macrophage phenotype characterized by arginase-1 and IL-10. Leprdb\/db mice showed increased left ventricular M1 phenotype macrophages and an increase in the M1\/M2 ratio. Replacement SP in Leprdb\/db mice restored a favorable M1 to M2 balance. Together these findings indicate that a loss of SP predisposes the diabetic heart to developing fibrosis. The anti-fibrotic actions of replacement SP involve direct effects on cardiac fibroblasts and macrophages to oppose adverse phenotype changes. This study identifies the potential of replacement SP to treat diabetic cardiomyopathy.<\/jats:p>","DOI":"10.3390\/cells10102659","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T09:24:04Z","timestamp":1633598644000},"page":"2659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Replacement of Lost Substance P Reduces Fibrosis in the Diabetic Heart by Preventing Adverse Fibroblast and Macrophage Phenotype Changes"],"prefix":"10.3390","volume":"10","author":[{"given":"Alexander","family":"Widiapradja","sequence":"first","affiliation":[{"name":"Kolling Institute, St Leonards, NSW 2065, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainsley O.","family":"Kasparian","sequence":"additional","affiliation":[{"name":"Kolling Institute, St Leonards, NSW 2065, Australia"},{"name":"School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2455-7551","authenticated-orcid":false,"given":"Samuel L.","family":"McCaffrey","sequence":"additional","affiliation":[{"name":"Kolling Institute, St Leonards, NSW 2065, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren L.","family":"Kolb","sequence":"additional","affiliation":[{"name":"Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Imig","sequence":"additional","affiliation":[{"name":"Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Lacey","sequence":"additional","affiliation":[{"name":"Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Section on Comparative Medicine, Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3760-3812","authenticated-orcid":false,"given":"Giselle C.","family":"Melendez","sequence":"additional","affiliation":[{"name":"Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"},{"name":"Section on Comparative Medicine, Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5034-4942","authenticated-orcid":false,"given":"Scott P.","family":"Levick","sequence":"additional","affiliation":[{"name":"Kolling Institute, St Leonards, NSW 2065, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/j.jacc.2018.01.047","article-title":"Prevalent and Incident Heart Failure in Cardiovascular Outcome Trials of Patients with Type 2 Diabetes","volume":"71","author":"Greene","year":"2018","journal-title":"J. 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