{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:01:56Z","timestamp":1790402516150,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,8,30]],"date-time":"2016-08-30T00:00:00Z","timestamp":1472515200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008349","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2016,12]]},"abstract":"\n Aim<\/jats:title>\n \n To test the effect of linagliptin in non\u2010obese diabetic (\n NOD<\/jats:styled-content>\n ) mice, a murine model of type 1 diabetes, to unveil a possible direct cardiovascular action of dipeptidyl peptidase 4 (\n DPP<\/jats:styled-content>\n \u20104) inhibitors beyond glycaemia control.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n NOD<\/jats:styled-content>\n mice were grouped according to glycosuria levels as\n NODI<\/jats:styled-content>\n : none;\n NODII<\/jats:styled-content>\n : high;\n NODIII<\/jats:styled-content>\n : severe. Linagliptin treatment was initiated once they reached\n NODII<\/jats:styled-content>\n levels. Vascular reactivity was assessed\n ex vivo<\/jats:italic>\n on aorta harvested from mice upon reaching\n NODIII<\/jats:styled-content>\n level. In a separate set of experiments, the effect of linagliptin was tested directly\n in vitro<\/jats:italic>\n on vessels harvested from untreated\n NODIII<\/jats:styled-content>\n , glucagon\u2010like peptide\u20101 (\n GLP<\/jats:styled-content>\n \u20101) receptor knockout and soluble guanylyl cyclase\u2010\u03b11 knockout mice. Molecular and cellular studies were performed on endothelial and endothelial nitric oxide synthase (\n eNOS<\/jats:styled-content>\n )\u2010transfected cells.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In this\n ex vivo<\/jats:italic>\n vascular study, endothelium\u2010dependent vasorelaxation was ameliorated and\n eNOS<\/jats:styled-content>\n \/nitric oxide (\n NO<\/jats:styled-content>\n )\/soluble guanylyl cyclase (\n sGC<\/jats:styled-content>\n ) signalling was enhanced. In the\n in vitro<\/jats:italic>\n vascular study, linagliptin exerted a direct vasodilating activity on vessels harvested from both normo\u2010 or hyperglycaemic mice. The effect was independent from\n GLP<\/jats:styled-content>\n \u20101\/\n GLP<\/jats:styled-content>\n \u20101 receptor (\n GLP\u20101R<\/jats:styled-content>\n ) interaction and required\n eNOS<\/jats:styled-content>\n \/\n NO<\/jats:styled-content>\n \/\n sGC<\/jats:styled-content>\n pathway activation. Molecular studies performed on endothelial cells show that linagliptin rescues\n eNOS<\/jats:styled-content>\n from caveolin\u20101 (\n CAV<\/jats:styled-content>\n \u20101)\u2010binding in a calcium\u2010independent manner.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Linagliptin, by interfering with the protein\u2013protein interaction\n CAV<\/jats:styled-content>\n \u20101\/\n eNOS<\/jats:styled-content>\n , led to an increased\n eNOS<\/jats:styled-content>\n availability, thus enhancing\n NO<\/jats:styled-content>\n production. This mechanism accounts for the vascular effect of linagliptin that is independent from glucose control and\n GLP<\/jats:styled-content>\n \u20101\/\n GLP\u20101R<\/jats:styled-content>\n interaction.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/dom.12750","type":"journal-article","created":{"date-parts":[[2016,7,27]],"date-time":"2016-07-27T03:59:03Z","timestamp":1469591943000},"page":"1236-1243","source":"Crossref","is-referenced-by-count":36,"title":["Vascular effects of linagliptin in non\u2010obese diabetic mice are glucose\u2010independent and involve positive modulation of the endothelial nitric oxide synthase (\n eNOS<\/scp>\n )\/caveolin\u20101 (\n CAV<\/scp>\n \u20101) pathway"],"prefix":"10.1111","volume":"18","author":[{"given":"Valentina","family":"Vellecco","sequence":"first","affiliation":[{"name":"Department of Pharmacy University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Mitidieri","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Gargiulo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Brancaleone","sequence":"additional","affiliation":[{"name":"Department of Science University of Basilicata Potenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danilo","family":"Matassa","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klein","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG Cardio\u2010metabolic Diseases Ingelheim am Rhein Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franca","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Cirino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarosaria","family":"Bucci","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,8,30]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.01.004"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.04.008"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2014-1035"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-013-6459-8"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.09.050"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2012.01.398"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.096479"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-011-0665-3"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.2337\/db09-0955"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.07.053"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-1855"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070933"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1939-1676.2012.00942.x"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2011.03.001"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs246"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02102.x"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.112.195115"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.287.11.1420"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(01)02063-X"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc10-0187"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.223.133"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.739938"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.12.075"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2008.08.001"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/590456"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1538\/expanim1978.29.1_1"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000122362.44628.09"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1993.1449"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2008.06.002"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(02)00078-5"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvn068"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01165"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1540\/jsmr.38.87"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2011.02.008"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12641"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(99)00094-2"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr304"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.2165\/11630900-000000000-00000"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00057.2016"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fdom.12750","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fdom.12750","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/pdf\/10.1111\/dom.12750","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:53:24Z","timestamp":1761864804000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/10.1111\/dom.12750"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,30]]},"references-count":39,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016,12]]}},"alternative-id":["10.1111\/dom.12750"],"URL":"https:\/\/doi.org\/10.1111\/dom.12750","archive":["Portico"],"relation":{},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,30]]}}}