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As both innate and adaptive immune cells play critical roles in the formation and progression of arterial plaques and endothelial cell dysfunction, CAD is commonly viewed as a chronic inflammatory disorder. Our lab has previously discovered that 5-HT<jats:sub>2A<\/jats:sub> receptor activation with the 5-HT<jats:sub>2<\/jats:sub> receptor selective agonist (<jats:italic>R<\/jats:italic>)-2,5-dimethoxy-4-iodoamphetamine [(<jats:italic>R<\/jats:italic>)-DOI] has potent anti-inflammatory activity in both cell culture and whole animal models. Here we have examined the putative therapeutic effects of (<jats:italic>R<\/jats:italic>)-DOI in the ApoE<jats:sup>\u2212\/\u2212<\/jats:sup> high fat model of cardiovascular disease. Subcutaneously implanted osmotic minipumps were used to infuse sustained low rates (0.15\u2009\u03bcg \/ hr) of (<jats:italic>R<\/jats:italic>)-DOI\u2219HCl to mice fed a high-fat \u201cWestern\u201d diet. (<jats:italic>R<\/jats:italic>)-DOI treated mice had significant reductions in expression levels of mRNA for inflammatory markers like <jats:italic>Il<\/jats:italic>6 in vascular tissue, normalized glucose homeostasis, and reduced circulating cholesterol levels. As cardiovascular disease is a leading cause of death both globally and in the Western world, activation of 5-HT<jats:sub>2A<\/jats:sub> receptors at sub-behavioral levels may represent a new strategy to treat inflammation-based cardiovascular disease.<\/jats:p>","DOI":"10.1038\/s41598-019-49987-0","type":"journal-article","created":{"date-parts":[[2019,9,17]],"date-time":"2019-09-17T10:04:52Z","timestamp":1568714692000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Activation of 5-HT2 Receptors Reduces Inflammation in Vascular Tissue and Cholesterol Levels in High-Fat Diet-Fed Apolipoprotein E Knockout Mice"],"prefix":"10.1038","volume":"9","author":[{"given":"Thomas W.","family":"Flanagan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melaine N.","family":"Sebastian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M.","family":"Battaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy P.","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeline L.","family":"Maillet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles D.","family":"Nichols","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,17]]},"reference":[{"key":"49987_CR1","doi-asserted-by":"publisher","first-page":"2459","DOI":"10.1093\/eurheartj\/ehx144","volume":"38","author":"BA Ference","year":"2017","unstructured":"Ference, B. 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