{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T20:49:50Z","timestamp":1776199790602,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015993","name":"Kowa Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015993","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Epidemiological and animal studies have revealed that sodium\u2010glucose cotransporter 2 (SGLT2) inhibitors suppress cardiovascular events in subjects with type 2 diabetes and atherosclerosis in animal models of diabetes. However, it still remains unclear if the anti\u2010atherosclerotic effect of SGLT2 inhibitors is entirely dependent on their glucose\u2010lowering effect. Tofogliflozin, a highly specific SGLT2 inhibitor, was administrated to apolipoprotein\u2010E\u2010deficient (ApoEKO) with streptozotocin (STZ)\u2010induced diabetes and nondiabetic ApoEKO mice. After 6 weeks, samples were collected to investigate the histological changes and peritoneal macrophage inflammatory cytokine levels. Tofogliflozin suppressed atherosclerosis in the diabetic ApoEKO mice. The atherosclerosis lesion areas and accumulation of macrophages in these areas were reduced by tofogliflozin treatment. The expression levels of interleukin (IL)\u20101\u03b2 and IL\u20106 in the peritoneal macrophages were significantly suppressed in the tofogliflozin\u2010treated diabetic ApoEKO mice. Tofogliflozin treatment failed to inhibit atherosclerosis in the nondiabetic ApoEKO mice. No significant difference in the anti\u2010atherosclerotic effects of insulin and tofogliflozin was observed between diabetic ApoEKO mice with equivalent degrees of glycemic control achieved with the two treatments. Insulin treatment significantly reduced the IL\u20101\u03b2 and IL\u20106 expression levels in the peritoneal macrophages of the diabetic ApoEKO mice. Significant decrease of the LPS\u2010stimulated IL\u20101\u03b2 concentrations was also observed in the conditioned medium of the peritoneal macrophages collected from insulin\u2010 and tofogliflozin\u2010treated diabetic ApoEKO mice. These results suggest that tofogliflozin suppresses atherosclerosis by improving glucose intolerance associated with inhibition of inflammation. Tofogliflozin suppresses atherosclerosis in ApoEKO mice with STZ\u2010induced diabetes via its glucose\u2010lowering effect.<\/jats:p>","DOI":"10.1002\/prp2.971","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T06:25:42Z","timestamp":1655360742000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The sodium\u2010glucose co\u2010transporter 2 inhibitor tofogliflozin suppresses atherosclerosis through glucose lowering in ApoE\u2010deficient mice with streptozotocin\u2010induced diabetes"],"prefix":"10.1002","volume":"10","author":[{"given":"Masahiko","family":"Iwamoto","sequence":"first","affiliation":[{"name":"Department of Diabetes and Metabolic Diseases Graduate School of Medicine The University of Tokyo  Tokyo Japan"},{"name":"Division of Diabetes and Metabolism The Institute of Medical Science Asahi Life Foundation  Tokyo 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