MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen Sulfide
Reduced angiotensin 1–7 bioavailability due to inhibition of angiotensin-converting enzyme 2 (ACE2) may contribute to increased mortality in hypertensive individuals during COVID-19. However, effects of ACE2 inhibitor MLN-4760 in brain functions remain unknown. We investigated the selected behaviour...
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MDPI AG
2022-12-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/12/2385 |
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| author | Michal Kluknavsky Andrea Micurova Martina Cebova Ezgi Şaman Sona Cacanyiova Iveta Bernatova |
| author_facet | Michal Kluknavsky Andrea Micurova Martina Cebova Ezgi Şaman Sona Cacanyiova Iveta Bernatova |
| author_sort | Michal Kluknavsky |
| collection | DOAJ |
| description | Reduced angiotensin 1–7 bioavailability due to inhibition of angiotensin-converting enzyme 2 (ACE2) may contribute to increased mortality in hypertensive individuals during COVID-19. However, effects of ACE2 inhibitor MLN-4760 in brain functions remain unknown. We investigated the selected behavioural and hemodynamic parameters in spontaneously hypertensive rats (SHRs) after a 2-week s.c. infusion of MLN-4760 (dose 1 mg/kg/day). The biochemical and molecular effects of MLN-4760 were investigated in the brainstem and blood plasma. MLN-4760 had no effects on hemodynamic and behavioural parameters. However, MLN-4760 increased plasma hydrogen sulfide (H<sub>2</sub>S) level and total nitric oxide (NO) synthase activity and conjugated dienes in the brainstem. Increased NO synthase activity correlated positively with gene expression of <i>Nos3</i> while plasma H<sub>2</sub>S levels correlated positively with gene expressions of H<sub>2</sub>S-producing enzymes <i>Mpst</i>, <i>Cth</i> and <i>Cbs</i>. MLN-4760 administration increased gene expression of <i>Ace2</i>, <i>Sod1</i>, <i>Sod2</i>, <i>Gpx4</i> and <i>Hmox1</i>, which positively correlated with expression of <i>Nfe2l2</i> gene encoding the redox-sensitive transcription factor NRF2. Collectively, MLN-4760 did not exacerbate pre-existing hypertension and behavioural hyperactivity/anxiety in SHRs. However, MLN-4760-induced oxidative damage in brainstem was associated with activation of NO- and H<sub>2</sub>S-mediated compensatory mechanisms and with increased gene expression of antioxidant, NO- and H<sub>2</sub>S-producing enzymes that all correlated positively with elevated <i>Nfe2l2</i> expression. |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T17:23:57Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-58faea74ffa74fa098f819ce774bc5732023-11-24T12:57:07ZengMDPI AGAntioxidants2076-39212022-12-011112238510.3390/antiox11122385MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen SulfideMichal Kluknavsky0Andrea Micurova1Martina Cebova2Ezgi Şaman3Sona Cacanyiova4Iveta Bernatova5Centre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, 841 04 Bratislava, SlovakiaCentre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, 841 04 Bratislava, SlovakiaCentre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, 841 04 Bratislava, SlovakiaCentre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, 841 04 Bratislava, SlovakiaCentre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, 841 04 Bratislava, SlovakiaCentre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, 841 04 Bratislava, SlovakiaReduced angiotensin 1–7 bioavailability due to inhibition of angiotensin-converting enzyme 2 (ACE2) may contribute to increased mortality in hypertensive individuals during COVID-19. However, effects of ACE2 inhibitor MLN-4760 in brain functions remain unknown. We investigated the selected behavioural and hemodynamic parameters in spontaneously hypertensive rats (SHRs) after a 2-week s.c. infusion of MLN-4760 (dose 1 mg/kg/day). The biochemical and molecular effects of MLN-4760 were investigated in the brainstem and blood plasma. MLN-4760 had no effects on hemodynamic and behavioural parameters. However, MLN-4760 increased plasma hydrogen sulfide (H<sub>2</sub>S) level and total nitric oxide (NO) synthase activity and conjugated dienes in the brainstem. Increased NO synthase activity correlated positively with gene expression of <i>Nos3</i> while plasma H<sub>2</sub>S levels correlated positively with gene expressions of H<sub>2</sub>S-producing enzymes <i>Mpst</i>, <i>Cth</i> and <i>Cbs</i>. MLN-4760 administration increased gene expression of <i>Ace2</i>, <i>Sod1</i>, <i>Sod2</i>, <i>Gpx4</i> and <i>Hmox1</i>, which positively correlated with expression of <i>Nfe2l2</i> gene encoding the redox-sensitive transcription factor NRF2. Collectively, MLN-4760 did not exacerbate pre-existing hypertension and behavioural hyperactivity/anxiety in SHRs. However, MLN-4760-induced oxidative damage in brainstem was associated with activation of NO- and H<sub>2</sub>S-mediated compensatory mechanisms and with increased gene expression of antioxidant, NO- and H<sub>2</sub>S-producing enzymes that all correlated positively with elevated <i>Nfe2l2</i> expression.https://www.mdpi.com/2076-3921/11/12/2385ACE2antioxidant enzymesoxidative damagenitric oxidehydrogen sulfideNRF2 |
| spellingShingle | Michal Kluknavsky Andrea Micurova Martina Cebova Ezgi Şaman Sona Cacanyiova Iveta Bernatova MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen Sulfide Antioxidants ACE2 antioxidant enzymes oxidative damage nitric oxide hydrogen sulfide NRF2 |
| title | MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen Sulfide |
| title_full | MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen Sulfide |
| title_fullStr | MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen Sulfide |
| title_full_unstemmed | MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen Sulfide |
| title_short | MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of <i>Nfe2l2</i> Gene, Nitric Oxide and Hydrogen Sulfide |
| title_sort | mln 4760 induces oxidative stress without blood pressure and behavioural alterations in shrs roles of i nfe2l2 i gene nitric oxide and hydrogen sulfide |
| topic | ACE2 antioxidant enzymes oxidative damage nitric oxide hydrogen sulfide NRF2 |
| url | https://www.mdpi.com/2076-3921/11/12/2385 |
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