{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:01:21Z","timestamp":1791806481523,"version":"4.3.4"},"reference-count":35,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["BT\/PR23486\/BRB\/10\/1589\/2017"],"award-info":[{"award-number":["BT\/PR23486\/BRB\/10\/1589\/2017"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Biotechnology, Government of India","award":["BT\/PR23486\/BRB\/10\/1589\/2017"],"award-info":[{"award-number":["BT\/PR23486\/BRB\/10\/1589\/2017"]}]},{"name":"Kerala State Council for Science, Technology and Environment","award":["BT\/PR23486\/BRB\/10\/1589\/2017"],"award-info":[{"award-number":["BT\/PR23486\/BRB\/10\/1589\/2017"]}]},{"name":"Intramural Research Program of the National Institute on Aging, National Institutes of Health","award":["BT\/PR23486\/BRB\/10\/1589\/2017"],"award-info":[{"award-number":["BT\/PR23486\/BRB\/10\/1589\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Molecular mechanisms underlying the diverse therapeutic effects of anti-diabetic metformin, beyond its anti-hyperglycaemic effects, remain largely unclear. Metformin is reported to reduce the long-term complications of diabetes, including cardiovascular fibrosis and remodelling. Our recent investigations show that Discoidin Domain Receptor 2 (DDR2), a Collagen receptor tyrosine kinase, has an obligate regulatory role in Collagen type I gene expression in cardiac and vascular adventitial fibroblasts, and that it may be a molecular link between arterial fibrosis and metabolic syndrome in rhesus monkeys. Using gene knockdown and overexpression approaches, the present study examined whether DDR2 is a target of metformin and whether, by targeting DDR2, it inhibits Fibronectin and Collagen type I expression in rat aortic adventitial fibroblasts exposed to hyperglycaemic conditions. Metformin was found to attenuate hyperglycaemia-induced increase in DDR2 mRNA and protein expression by inhibiting TGF-\u03b21\/SMAD2\/3 signalling that mediates the stimulatory effect of hyperglycaemia on DDR2 expression. Metformin also inhibited DDR2-dependent expression of Fibronectin and Collagen type I, indicating that it regulates these matrix proteins via DDR2 inhibition. The findings identify DDR2, a mediator of cardiovascular remodelling, as a molecular target of metformin, thereby uncovering the molecular basis of its protective role in vascular fibrosis and possibly cardiac fibrosis associated with diabetic cardiomyopathy.<\/jats:p>","DOI":"10.3390\/ijms24010585","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:26:11Z","timestamp":1672370771000},"page":"585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Metformin Attenuates Hyperglycaemia-Stimulated Pro-Fibrotic Gene Expression in Adventitial Fibroblasts via Inhibition of Discoidin Domain Receptor 2"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8149-3895","authenticated-orcid":false,"given":"Allen Sam","family":"Titus","sequence":"first","affiliation":[{"name":"Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mereena George","family":"Ushakumary","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harikrishnan","family":"Venugopal","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6412-369X","authenticated-orcid":false,"given":"Mingyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science, National Institute on Aging\/National Institutes of Health, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward G.","family":"Lakatta","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science, National Institute on Aging\/National Institutes of Health, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivakumar","family":"Kailasam","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, University of Kerala, Kariavattom, Trivandrum 695581, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.2147\/DDDT.S141675","article-title":"Metformin: A Review of Its Potential Indications","volume":"11","author":"Wang","year":"2017","journal-title":"Drug Des. 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