The Keap1/Nrf2/ARE system activators do not increase cardiac resistance to long-term ischemia/reperfusion

Abstract

Oxidative stress is an important mechanism of myocardial damage during ischemia/reperfusion. To investigate the possibility of restoring the redox balance using “indirect” antioxidant effects, the cardioprotective effect Keap1/Nrf2/ ARE system inducers was studied in long-term ischemia/reperfusion in vivo. Material and methods. We used the original synthetic hydrophilic monophenol sodium 3-(3’-tert-butyl-4’-hydroxyphenyl) propyl thiosulfonate (TS-13) and reference drug tert-butylhydroquinone (tBHQ). Male Wistar rats received 100 mg/kg of TS-13 solution (with drinking water) or tBHQ (intraperitoneally) daily for 7 days. Animals of the comparison groups received the corresponding solvents. Local ischemia (45 min, occlusion of the left coronary artery) and reperfusion (120 min) of the heart were simulated in vivo 1 day after last drug administration. The ECG was recorded during ischemia and reperfusion; at the end of reperfusion, the heart was removed, the zone of hypoperfusion and the zone of necrosis were detected. Changes in the expression of the mRNA of Nfe2l2, Nqo1, Hmox1, Gstp1, Rela, and Nfkb2 gene in myocardial tissue were determined by real-time TaqMan PCR. Results and discussion. Pretreatment with TS-13 and tBHQ did not influence the infarct size and the incidence of ventricular arrhythmias. Preliminary administration of tBHQ did not change the genes expression of the studied in myocardial tissue after prolonged I/R. TS-13 administration was accompanied by an increase in the content of the transcripts of the gene that encodes Nrf2 (by 7.64 times) and Nrf2-driven genes Nqo1 (by 6.46 times) and Hmox1 (by 3.63 times); the expression of the Gstp1, Rela, and Nfkb2 genes did not differ from the corresponding values of the control group; compared to animals treated with tBHQ, the expression of the Nfe2l2, Nqo1, Hmox1, Rela, and Nfkb2 genes was 16.23, 4.44, 2.68, 3.17, and 2.64 times higher, respectively. The results obtained cast doubt on the therapeutic importance of the induction of the Keap1/Nrf2/ARE system during prolonged heart ischemia/reperfusion.