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Cardioprotective effects of quercetin (Q) have mostly been evaluated in ischemic heart disease models and attributed to senolysis. We hypothesized that Q could alleviate murine cardiac damage caused by HFD by restoring the myocardial microcirculation. C57BL\/6J mice were fed standard chow or HFD for 6 months and then treated with Q (50\u2009mg\/kg) or vehicle 5\u2010day biweekly for 10 additional weeks. Left ventricular (LV) cardiac function was studied in vivo using magnetic resonance imaging, and intramyocardial fat deposition, microvascular density, oxidative stress, and senescence were analyzed ex vivo. Additionally, direct angiogenic effects of Q were studied in vitro in HUVECs. HFD increased body weight, heart weight, total cholesterol, and triglyceride levels, whereas Q normalized heart weight and triglycerides. LV ejection fraction was lower in HFD vs. control mice (56.20 \u00b1 15.8<jats:italic>%<\/jats:italic> vs. 73.38 \u00b1 5.04<jats:italic>%<\/jats:italic>, respectively, <jats:italic>P<\/jats:italic> &lt; 0.05), but improved in HFD\u2009+\u2009Q mice (67.42 \u00b1 7.50<jats:italic>%<\/jats:italic>, <jats:italic>P<\/jats:italic> &lt; 0.05, vs. HFD). Q also prevented cardiac fat accumulation and reduced HFD\u2010induced cardiac fibrosis, cardiomyocyte hypertrophy, oxidative stress, and vascular rarefaction. Cardiac senescence was not observed in any group. In vitro, ox\u2010LDL reduced HUVEC tube formation activity, which Q effectively improved. Quercetin may directly induce angiogenesis and decrease myocardial oxidative stress, which might account for its cardioprotective effects in the murine HFD\u2010fed murine heart independently from senolytic activity. Furthermore, its beneficial effects might be partly attributed to a decrease in plasma triglycerides and intramyocardial fat deposition.<\/jats:p>","DOI":"10.1155\/2021\/8875729","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T20:23:39Z","timestamp":1613852619000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Quercetin Reverses Cardiac Systolic Dysfunction in Mice Fed with a High\u2010Fat Diet: Role of Angiogenesis"],"prefix":"10.1155","volume":"2021","author":[{"given":"Shasha","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3552-0519","authenticated-orcid":false,"given":"Seo 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