{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T19:47:54Z","timestamp":1767988074284,"version":"3.49.0"},"reference-count":44,"publisher":"American Diabetes Association","issue":"11","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":4398,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,11,1]]},"abstract":"<jats:sec><jats:title>OBJECTIVE<\/jats:title><jats:p>Vascular endothelial growth factor (VEGF), which is associated with the stimulation of angiogenesis and collateral vessel synthase, is one of the crucial factors involved in cardiac remodeling in type 2 diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESEARCH DESIGN AND METHODS<\/jats:title><jats:p>We investigated VEGF inhibition by dRK6 on the heart in an animal model of type 2 diabetes. Male db\/db and db\/m mice either were treated with dRK6 starting at 7 weeks of age for 12 weeks (db\/db-dRK6 and db\/m-dRK6) or were untreated.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Cardiac dysfunction and hypertrophy were noted by echocardiogram and molecular markers in the db\/db-dRK6 mice. The presence of diabetes significantly suppressed the expression of VEGF receptor (VEGFR)-1 and VEGFR-2, phospho-Akt, and phospho-endothelial nitric oxide synthase (eNOS) in the heart. In db\/db-dRK6 mice, dRK6 completely inhibited VEGFR-2, phospho-Akt, and phospho-eNOS expression, whereas no effect on VEGFR-1 was observed. Cardiac fibrosis, microvascular scarcity associated with an increase in apoptotic endothelial cells, and inflammation were prominent, as well as increase in antiangiogenic growth factors. Cardiac 8-hydroxy-deoxyguanine and hypoxia-inducible factor-1\u03b1 expression were significantly increased. No such changes were found in the other groups, including the db\/m-dRK6 mice. The number of apoptotic human umbilical vein endothelial cells was increased by dRK6 in a dose-dependent manner only at high glucose concentrations, and this was associated with a decrease in phospho-Akt and phospho-eNOS related to oxidative stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Our results demonstrated that systemic blockade of VEGF by dRK6 had deleterious effects on the heart in an animal model of type 2 diabetes; dRK6 induced downregulation of the VEGFR-2 and Akt-eNOS axis and enhancement of oxidative stress.<\/jats:p><\/jats:sec>","DOI":"10.2337\/db09-0136","type":"journal-article","created":{"date-parts":[[2009,8,13]],"date-time":"2009-08-13T01:38:14Z","timestamp":1250127494000},"page":"2666-2676","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":45,"title":["Vascular Endothelial Growth Factor Inhibition by dRK6 Causes Endothelial Apoptosis, Fibrosis, and Inflammation in the Heart via the Akt\/eNOS Axis in<i>db\/db<\/i>Mice"],"prefix":"10.2337","volume":"58","author":[{"given":"Cheol","family":"Whee Park","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyung","family":"Wook Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji","family":"Hee Lim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ki","family":"Dong Yoo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sungjin","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seok","family":"Joon Shin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun","family":"Wha Chung","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang","family":"Ju Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The Catholic University of Korea, Seoul, 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