{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T01:26:55Z","timestamp":1789349215723,"version":"build-2803163510"},"reference-count":64,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2015,8,10]],"date-time":"2015-08-10T00:00:00Z","timestamp":1439164800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000273","name":"Diabetes Wellness Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000273","id-type":"DOI","asserted-by":"crossref"}]},{"name":"G\u00e4stforskarstipendier Program of the Wenner-Gren Foundation"},{"name":"Karolinska Institutet\/Stockholm County Council Strategic Cardiovascular Programme"},{"name":"King Gustav V and Queen Victoria Foundation"},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Swedish Research Council (10857)"},{"name":"The Swedish Heart and Lung Foundation"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,10]]},"abstract":"Background and Purpose<\/jats:title>Emerging evidence suggests a selective up\u2010regulation of arginase I<\/jats:styled-content> in diabetes causing coronary artery disease; however, the mechanisms behind this up\u2010regulation are still unknown. Activated p38 MAPK<\/jats:styled-content> has been reported to increase arginase II<\/jats:styled-content> in various cardiovascular diseases. We therefore tested the role of p38 MAPK<\/jats:styled-content> in the regulation of arginase I<\/jats:styled-content> and II<\/jats:styled-content> expression and its effect on endothelial dysfunction in diabetes mellitus.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>Endothelial function was determined in septal coronary (SCA<\/jats:styled-content>), left anterior descending coronary (LAD<\/jats:styled-content>) and mesenteric (MA<\/jats:styled-content>) arteries from healthy and streptozotocin\u2010induced diabetic W<\/jats:styled-content>istar rats by wire myographs. Arginase activity and protein levels of arginase I<\/jats:styled-content>, II<\/jats:styled-content>, phospho\u2010p38 MAPK<\/jats:styled-content> and phospho\u2010endothelial NOS<\/jats:styled-content> (eNOS<\/jats:styled-content>) (S<\/jats:styled-content>er1177<\/jats:sup>) were determined in these arteries from diabetic and healthy rats treated with a p38 MAPK<\/jats:styled-content> inhibitor in vivo<\/jats:italic>.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Diabetic SCA<\/jats:styled-content> and MA<\/jats:styled-content> displayed impaired endothelium\u2010dependent relaxation, which was prevented by arginase and p38 MAPK<\/jats:styled-content> inhibition while LAD<\/jats:styled-content> relaxation was not affected. Arginase I<\/jats:styled-content>, phospho\u2010p38 MAPK<\/jats:styled-content> and eNOS<\/jats:styled-content> protein expression was increased in diabetic coronary arteries. In diabetic MA<\/jats:styled-content>, however, increased expression of arginase II<\/jats:styled-content> and phospho\u2010p38 MAPK<\/jats:styled-content>, increased arginase activity and decreased expression of eNOS<\/jats:styled-content> were observed. All these effects were reversed by p38 MAPK<\/jats:styled-content> inhibition.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Diabetes\u2010induced activation of p38 MAPK<\/jats:styled-content> causes endothelial dysfunction via selective up\u2010regulation of arginase I<\/jats:styled-content> expression in coronary arteries and arginase II<\/jats:styled-content> expression in MA<\/jats:styled-content>. Therefore, regional differences appear to exist in the arginase isoforms contributing to endothelial dysfunction in type 1 diabetes mellitus.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13242","type":"journal-article","created":{"date-parts":[[2015,7,3]],"date-time":"2015-07-03T16:06:32Z","timestamp":1435939592000},"page":"4684-4698","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Tissue\u2010specific up\u2010regulation of arginase I<\/scp> and II<\/scp> induced by p38 MAPK<\/scp> mediates endothelial dysfunction in type 1 diabetes mellitus"],"prefix":"10.1111","volume":"172","author":[{"given":"J","family":"Pernow","sequence":"first","affiliation":[{"name":"Division of Cardiology Department of Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Kiss","sequence":"additional","affiliation":[{"name":"Division of 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