Thioredoxin-1 is required for the cardioprotecive effect of sildenafil against ischaemia/reperfusion injury and mitochondrial dysfunction in mice.

Abstract

Sildenafil is a phosphodiesterase type 5 inhibitor which confers cardioprotection against myocardial ischaemia/reperfusion (I/R) injury. The aim of this study was to determine if Trx1 participates in cardioprotection exerted by sildenafil in an acute model of I/R, and to evaluate mitochondrial bioenergetics and cellular redox status. Langendorff-perfused hearts from wild type (WT) mice and a dominant negative (DN-Trx1) mutant of Trx1 were assigned to placebo or sildenafil (0.7 mg/kg i.p.) and subjected to 30 min of ischaemia followed by 120 min of reperfusion. WT + S showed a significant reduction of infarct size (51.2 ± 3.0% vs. 30 ± 3.0%, p < .001), an effect not observed in DN-Trx. After I/R, sildenafil preserved state 3 oxygen consumption from WT, but had a milder effect in DN-Trx1 only partially protecting state 3 values. Treatment restored respiratory control (RC) after I/R, which resulted 8% (WT) and 24% (DN-Trx1) lower than in basal conditions. After I/R, a significant increase in H2O2 production was observed both for WT and DN-Trx (WT: 1.17 ± 0.13 nmol/mg protein and DN-Trx: 1.38 ± 0.12 nmol/min mg protein). With sildenafil, values were 21% lower only in WT I/R. Treatment decreased GSSG levels both in WT and DN-Trx1. In addition, GSSG/GSH2 ratio was partially restored by sildenafil. Also, an increase in p-eNOS/eNOS even before the myocardial ischaemia was observed with sildenafil, both in WT (14%, p > .05) and in DN-Trx (35%, p < .05). Active Trx1 is required for the onset of the cardioprotective effects of sildenafil on I/R injury, together with the preservation of cellular redox balance and mitochondrial function.

• Authors: Tamara Zaobornyj, Tamara Mazo, Virginia Perez, Anabella Gomez, Mario Contin, Valeria Tripodi, Verónica D'Annunzio, Ricardo J Gelpi
• Journal: Free radical research (Free Radic Res) Vol. 53 Issue 9-10 Pg. 993-1004 (Oct 2019) ISSN: 1029-2470 [Electronic] England
• PMID: 31455116 (Publication Type: Journal Article)

Chemical References

• Phosphodiesterase 5 Inhibitors
• Sildenafil Citrate

Topics

• Animals
• Male
• Mice
• Mice, Transgenic
• Mitochondria (drug effects)
• Myocardial Ischemia (drug therapy)
• Myocardial Reperfusion Injury (drug therapy)
• Phosphodiesterase 5 Inhibitors (pharmacology, therapeutic use)
• Sildenafil Citrate (pharmacology, therapeutic use)