Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1α via downregulation of prolyl hydroxylase 3

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)-1α in such a...

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Published in:	American journal of physiology. Heart and circulatory physiology 2018-11, Vol.315 (5), p.H1148-H1158
Main Authors:	Neckář, Jan, Hsu, Anna, Hye Khan, Md Abdul, Gross, Garrett J, Nithipatikom, Kasem, Cyprová, Michaela, Benák, Daniel, Hlaváčková, Markéta, Sotáková-Kašparová, Dita, Falck, John R, Sedmera, David, Kolář, František, Imig, John D
Format:	Article
Language:	eng
Subjects:	8,11,14-Eicosatrienoic Acid - analogs & derivatives 8,11,14-Eicosatrienoic Acid - pharmacology 8,11,14-Eicosatrienoic Acid - therapeutic use Acids Acriflavine Animals Constraining Coronary artery Degradation Disease Models, Animal Down-Regulation Drug administration Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Hypoxia-Inducible Factor-Proline Dioxygenases - genetics Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism Hypoxia-inducible factors Immunogenicity Immunoreactivity Inhibitor drugs Ischemia Male Myocardial infarction Myocardial Infarction - enzymology Myocardial Infarction - pathology Myocardial Infarction - physiopathology Myocardial Infarction - prevention & control Myocardial Reperfusion Injury - enzymology Myocardial Reperfusion Injury - pathology Myocardial Reperfusion Injury - physiopathology Myocardial Reperfusion Injury - prevention & control Myocardium - enzymology Myocardium - pathology Occlusion Prolyl hydroxylase Proteins Proteolysis Rats Rats, Sprague-Dawley Reperfusion Septum Signal Transduction - drug effects Ventricular Function, Left - drug effects Ventricular Remodeling - drug effects
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Summary:	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)-1α 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 ± 1.3% in control to 42.6 ± 1.9% and 46.0 ± 1.6%, 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 ± 1.1%). Similarly, the HIF-1α 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-1α 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-1α immunogenic signal markedly increased in the ischemic area compared with the septum (10.31 ± 0.78% vs. 0.34 ± 0.08%). After 20 min and 2 h of reperfusion, HIF-1α immunoreactivity decreased to 2.40 ± 0.48% and 1.85 ± 0.43%, respectively, in the controls. EET-B blunted the decrease of HIF-1α immunoreactivity (7.80 ± 0.69% and 6.44 ± 1.37%, 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-1α and downregulation of its degrading enzyme PHD3. NEW & 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-1α levels play a role in cardioprotection mediated by EET-B in reperfusion likely by mechanisms including downregulation of the hypoxia-inducible factor -1α-degrading enzyme prolyl hydroxylase domain protein 3.
ISSN:	0363-6135 1522-1539