Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion
The cardioprotective effects of nitric oxide (NO) have been described through S-nitrosylation of several important proteins in the mitochondria of the cardiomyocyte. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of S-nitrosothiols by producing denitrosylation, thus l...
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MDPI AG
2021-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/4/555 |
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| author | Oscar Arriagada Castillo Gustavo Herrera Carlos Manriquez Andrea F. Rojas Daniel R. González |
| author_facet | Oscar Arriagada Castillo Gustavo Herrera Carlos Manriquez Andrea F. Rojas Daniel R. González |
| author_sort | Oscar Arriagada Castillo |
| collection | DOAJ |
| description | The cardioprotective effects of nitric oxide (NO) have been described through S-nitrosylation of several important proteins in the mitochondria of the cardiomyocyte. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of S-nitrosothiols by producing denitrosylation, thus limiting the cardioprotective effect of NO. The effect of GSNOR inhibition on the damage by cardiac ischemia–reperfusion is still unclear. We tested the hypothesis that pharmacological inhibition of GSNOR promotes cardioprotection by increasing the levels of protein S-nitrosylation. In a model of ischemia–reperfusion in isolated rat heart, the effect of a GSNOR inhibitor, 5-chloro-3-(2-[4-ethoxyphenyl) (ethyl) amino]-2-oxoethyl)-1H-indole-2-carboxylic acid (C2), was investigated. Ventricular function and hemodynamics were determined, in addition to tissue damage and S-nitrosylation of mitochondrial proteins. Hearts treated with C2 showed a lower release of myocardial damage marker creatine kinase and a reduction in the infarcted area. It also improved post-ischemia ventricular function compared to controls. These results were associated with increasing protein S-nitrosylation, specifically of the mitochondrial complexes III and V. The pharmacological inhibition of GSNOR showed a concentration-dependent cardioprotective effect, being observed in functional parameters and myocardial damage, which was maximal at 1 µmol/L, associated with increased S-nitrosylation of mitochondrial proteins. These data suggest that GSNOR is an interesting pharmacological target for cardiac reperfusion injury. |
| first_indexed | 2024-03-10T12:39:20Z |
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| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T12:39:20Z |
| publishDate | 2021-04-01 |
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| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-1c4e1654d1ba4a2dbfab98afb51f1c212023-11-21T14:00:31ZengMDPI AGAntioxidants2076-39212021-04-0110455510.3390/antiox10040555Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–ReperfusionOscar Arriagada Castillo0Gustavo Herrera1Carlos Manriquez2Andrea F. Rojas3Daniel R. González4Department of Basic Biomedical Sciences, School of Health Sciences, University of Talca, Talca 3460000, ChileDepartment of Basic Biomedical Sciences, School of Health Sciences, University of Talca, Talca 3460000, ChileDepartment of Basic Biomedical Sciences, School of Health Sciences, University of Talca, Talca 3460000, ChileDepartment of Basic Biomedical Sciences, School of Health Sciences, University of Talca, Talca 3460000, ChileDepartment of Basic Biomedical Sciences, School of Health Sciences, University of Talca, Talca 3460000, ChileThe cardioprotective effects of nitric oxide (NO) have been described through S-nitrosylation of several important proteins in the mitochondria of the cardiomyocyte. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of S-nitrosothiols by producing denitrosylation, thus limiting the cardioprotective effect of NO. The effect of GSNOR inhibition on the damage by cardiac ischemia–reperfusion is still unclear. We tested the hypothesis that pharmacological inhibition of GSNOR promotes cardioprotection by increasing the levels of protein S-nitrosylation. In a model of ischemia–reperfusion in isolated rat heart, the effect of a GSNOR inhibitor, 5-chloro-3-(2-[4-ethoxyphenyl) (ethyl) amino]-2-oxoethyl)-1H-indole-2-carboxylic acid (C2), was investigated. Ventricular function and hemodynamics were determined, in addition to tissue damage and S-nitrosylation of mitochondrial proteins. Hearts treated with C2 showed a lower release of myocardial damage marker creatine kinase and a reduction in the infarcted area. It also improved post-ischemia ventricular function compared to controls. These results were associated with increasing protein S-nitrosylation, specifically of the mitochondrial complexes III and V. The pharmacological inhibition of GSNOR showed a concentration-dependent cardioprotective effect, being observed in functional parameters and myocardial damage, which was maximal at 1 µmol/L, associated with increased S-nitrosylation of mitochondrial proteins. These data suggest that GSNOR is an interesting pharmacological target for cardiac reperfusion injury.https://www.mdpi.com/2076-3921/10/4/555S-nitrosylationheartGSNORmitochondria |
| spellingShingle | Oscar Arriagada Castillo Gustavo Herrera Carlos Manriquez Andrea F. Rojas Daniel R. González Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion Antioxidants S-nitrosylation heart GSNOR mitochondria |
| title | Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion |
| title_full | Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion |
| title_fullStr | Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion |
| title_full_unstemmed | Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion |
| title_short | Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion |
| title_sort | pharmacological inhibition of s nitrosoglutathione reductase reduces cardiac damage induced by ischemia reperfusion |
| topic | S-nitrosylation heart GSNOR mitochondria |
| url | https://www.mdpi.com/2076-3921/10/4/555 |
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