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Ralph and Marian Falk Medical Research Trust Bank of America"},{"DOI":"10.13039\/100000928","name":"Robert A. Welch Foundation","doi-asserted-by":"crossref","award":["I-0011"],"award-info":[{"award-number":["I-0011"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation (Grantov\u00e1 agentura Cesk\u00e9 republiky)","doi-asserted-by":"publisher","award":["18-03207S"],"award-info":[{"award-number":["18-03207S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2018,11,1]]},"abstract":"<jats:p> Epoxyeicosatrienoic acids (EETs) decrease cardiac ischemia-reperfusion injury; however, the mechanism of their protective effect remains elusive. Here, we investigated the cardioprotective action of a novel EET analog, EET-B, in reperfusion and the role of hypoxia-inducible factor (HIF)-1\u03b1 in such action of EET-B. Adult male rats were subjected to 30 min of left coronary artery occlusion followed by 2 h of reperfusion. Administration of 14,15-EET (2.5 mg\/kg) or EET-B (2.5 mg\/kg) 5 min before reperfusion reduced infarct size expressed as a percentage of the area at risk from 64.3\u2009\u00b1\u20091.3% in control to 42.6\u2009\u00b1 1.9% and 46.0\u2009\u00b1\u20091.6%, respectively, and their coadministration did not provide any stronger effect. The 14,15-EET antagonist 14,15-epoxyeicosa-5( Z)-enoic acid (2.5 mg\/kg) inhibited the infarct size-limiting effect of EET-B (62.5\u2009\u00b1\u20091.1%). Similarly, the HIF-1\u03b1 inhibitors 2-methoxyestradiol (2.5 mg\/kg) and acriflavine (2 mg\/kg) completely abolished the cardioprotective effect of EET-B. In a separate set of experiments, the immunoreactivity of HIF-1\u03b1 and its degrading enzyme prolyl hydroxylase domain protein 3 (PHD3) were analyzed in the ischemic areas and nonischemic septa. At the end of ischemia, the HIF-1\u03b1 immunogenic signal markedly increased in the ischemic area compared with the septum (10.31\u2009\u00b1\u20090.78% vs. 0.34\u2009\u00b1\u20090.08%). After 20 min and 2 h of reperfusion, HIF-1\u03b1 immunoreactivity decreased to 2.40\u2009\u00b1\u20090.48% and 1.85\u2009\u00b1\u20090.43%, respectively, in the controls. EET-B blunted the decrease of HIF-1\u03b1 immunoreactivity (7.80\u2009\u00b1\u20090.69% and 6.44\u2009\u00b1\u20091.37%, respectively) and significantly reduced PHD3 immunogenic signal in ischemic tissue after reperfusion. In conclusion, EET-B provides an infarct size-limiting effect at reperfusion that is mediated by HIF-1\u03b1 and downregulation of its degrading enzyme PHD3. <\/jats:p><jats:p> NEW &amp; NOTEWORTHY The present study shows that EET-B is an effective agonistic 14,15-epoxyeicosatrienoic acid analog, and its administration before reperfusion markedly reduced myocardial infarction in rats. Most importantly, we demonstrate that increased hypoxia-inducible factor-1\u03b1 levels play a role in cardioprotection mediated by EET-B in reperfusion likely by mechanisms including downregulation of the hypoxia-inducible factor -1\u03b1-degrading enzyme prolyl hydroxylase domain protein 3. <\/jats:p>","DOI":"10.1152\/ajpheart.00726.2017","type":"journal-article","created":{"date-parts":[[2018,8,3]],"date-time":"2018-08-03T12:38:17Z","timestamp":1533299897000},"page":"H1148-H1158","source":"Crossref","is-referenced-by-count":26,"title":["Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1\u03b1 via downregulation of prolyl hydroxylase 3"],"prefix":"10.1152","volume":"315","author":[{"given":"Jan","family":"Neck\u00e1\u0159","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin"},{"name":"Department of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic"},{"name":"Center for Experimental Medicine, Institute for Clinical and Experimental Medicine Physiology, Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md. 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