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

0498726 - FGÚ 2019 RIV US eng J - Článek v odborném periodiku
Neckář, Jan - Hsu, A. - Khan, M. A. H. - Gross, G. J. - Nithipatikom, K. - Cyprová, Michaela - Benák, Daniel - Hlaváčková, Markéta - Sotáková-Kašparová, Dita - Falck, J. R. - Sedmera, David - Kolář, František - Imig, J. D.
Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1 alpha via downregulation of prolyl hydroxylase 3.
American Journal of Physiology-Heart and Circulatory Physiology. Roč. 315, č. 5 (2018), H1148-H1158. ISSN 0363-6135. E-ISSN 1522-1539
Grant CEP: GA ČR(CZ) GA15-07544S; GA ČR(CZ) GA18-03207S
Institucionální podpora: RVO:67985823
Klíčová slova: epoxyeicosatrienoic acid * heart * hypoxia-inducible factor-1alpha * ischemia-reperfusion * prolyl hydroxylase 3
Obor OECD: Physiology (including cytology)
Impakt faktor: 4.048, rok: 2018

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 alpha 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 percent-age of the area at risk from 64.3 +/- 1.3% in control to 42.6 +/- 1.9% and 46.0 +/- 11.6%, 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-1 alpha 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 HIE-1 alpha and its degrading enzyme prolyl hydroxylase domain protein 3 (PHD3) were analyzed in the ischemic areas and non ischemic septa. At the end of ischemia, the HIF-1 alpha 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-1 alpha immunoreactivity decreased to 2.40 +/- 0.48% and 1.85 +/- 0.43%, respectively, in the controls. EET-B blunted the decrease of HIF-1 alpha immunoreactivity (7.80 +/- 0.69% and 6.44 +/- 1.37%, respectively) and significantly reduced PHD3 inununogenic signal in ischemic tissue after reperfusion. In conclusion, EET-B provides an infarct size-limiting effect at reperfusion that is mediated by HIF-1 alpha and downregulation of its degrading enzyme PHD3.
Trvalý link: http://hdl.handle.net/11104/0291008