Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1α via downregulation of prolyl hydroxylase 3
| Autor: | Anna Hsu, Marketa Hlavackova, Dita Sotakova-Kasparova, Abdul H. Khan, Kasem Nithipatikom, Michaela Cyprová, Garrett J. Gross, John R. Falck, Jan Neckář, John D. Imig, František Kolář, Daniel Benák, David Sedmera |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Physiology Myocardial Infarction Down-Regulation Myocardial Reperfusion Injury 030204 cardiovascular system & hematology Pharmacology Epoxyeicosatrienoic acid Ventricular Function Left Hypoxia-Inducible Factor-Proline Dioxygenases Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 8 11 14-Eicosatrienoic Acid 0302 clinical medicine Downregulation and upregulation Physiology (medical) medicine Animals Myocardial infarction Ventricular Remodeling Myocardium Limiting Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Infarct size Disease Models Animal 030104 developmental biology chemistry Hypoxia-inducible factors Proteolysis cardiovascular system lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine Signal Transduction Research Article |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 315:H1148-H1158 |
| ISSN: | 1522-1539 0363-6135 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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