Hydrocortisone cardioprotection in ischaemia/reperfusion injury involves antioxidant mechanisms
© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd..
BACKGROUND: Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue, and both can be activated by corticosteroids. MR activation, in acute myocardial infarction (AMI), worsens cardiac function, and increase NHE activity contributing to the deleterious process. In contrast, effects of GR activation are not fully understood, probably because of the controversial scenario generated by using different doses or potencies of corticosteroids.
AIMS: We tested the hypothesis that an acute dose of hydrocortisone (HC), a low-potency glucocorticoid, in a murine model of AMI could be cardioprotective by regulating NHE1 activity, leading to a decrease in oxidative stress.
MATERIALS AND METHODS: Isolated hearts from Wistar rats were subjected to regional ischemic protocol. HC (10 nmol/L) was added to the perfusate during early reperfusion. Infarct size and oxidative stress were determined. Isolated papillary muscles from non-infarcted hearts were used to evaluate HC effect on sodium-proton exchanger 1 (NHE1) by analysing intracellular pH recovery from acute transient acidosis.
RESULTS: HC treatment decreased infarct size, improved cardiac mechanics, reduced oxidative stress after AMI, while restoring the decreased level of the pro-fusion mitochondrial protein MFN-2. Co-treatment with the GR-blocker Mifepristone avoided these effects. HC reduced NHE1 activity by increasing the NHE1 pro-inhibiting Ser648 phosphorylation site and its upstream kinase AKT. HC restored the decreased AKT phosphorylation and anti-apoptotic BCL-2 protein expression detected after AMI.
CONCLUSIONS: Our results provide the first evidence that acute HC treatment during early reperfusion induces cardioprotection against AMI, associated with a non-genomic HC-triggered NHE1 inhibition by AKT and antioxidant action that might involves mitochondrial dynamics improvement.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:54 |
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| Enthalten in: |
European journal of clinical investigation - 54(2024), 5 vom: 29. Apr., Seite e14172 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Escudero, Daiana S [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.04.2024 Date Revised 17.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/eci.14172 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Hydrocortisone cardioprotection in ischaemia/reperfusion injury involves antioxidant mechanisms |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd. | ||
| 520 | |a BACKGROUND: Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue, and both can be activated by corticosteroids. MR activation, in acute myocardial infarction (AMI), worsens cardiac function, and increase NHE activity contributing to the deleterious process. In contrast, effects of GR activation are not fully understood, probably because of the controversial scenario generated by using different doses or potencies of corticosteroids | ||
| 520 | |a AIMS: We tested the hypothesis that an acute dose of hydrocortisone (HC), a low-potency glucocorticoid, in a murine model of AMI could be cardioprotective by regulating NHE1 activity, leading to a decrease in oxidative stress | ||
| 520 | |a MATERIALS AND METHODS: Isolated hearts from Wistar rats were subjected to regional ischemic protocol. HC (10 nmol/L) was added to the perfusate during early reperfusion. Infarct size and oxidative stress were determined. Isolated papillary muscles from non-infarcted hearts were used to evaluate HC effect on sodium-proton exchanger 1 (NHE1) by analysing intracellular pH recovery from acute transient acidosis | ||
| 520 | |a RESULTS: HC treatment decreased infarct size, improved cardiac mechanics, reduced oxidative stress after AMI, while restoring the decreased level of the pro-fusion mitochondrial protein MFN-2. Co-treatment with the GR-blocker Mifepristone avoided these effects. HC reduced NHE1 activity by increasing the NHE1 pro-inhibiting Ser648 phosphorylation site and its upstream kinase AKT. HC restored the decreased AKT phosphorylation and anti-apoptotic BCL-2 protein expression detected after AMI | ||
| 520 | |a CONCLUSIONS: Our results provide the first evidence that acute HC treatment during early reperfusion induces cardioprotection against AMI, associated with a non-genomic HC-triggered NHE1 inhibition by AKT and antioxidant action that might involves mitochondrial dynamics improvement | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AKT | |
| 650 | 4 | |a NHE1 | |
| 650 | 4 | |a cardioprotection | |
| 650 | 4 | |a glucocorticoids | |
| 650 | 4 | |a myocardial infarction | |
| 650 | 4 | |a oxidative stress | |
| 650 | 7 | |a Antioxidants |2 NLM | |
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| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Glucocorticoids |2 NLM | |
| 650 | 7 | |a Sodium-Hydrogen Exchangers |2 NLM | |
| 700 | 1 | |a Fantinelli, Juliana C |e verfasserin |4 aut | |
| 700 | 1 | |a Martínez, Valeria R |e verfasserin |4 aut | |
| 700 | 1 | |a González Arbeláez, Luisa F |e verfasserin |4 aut | |
| 700 | 1 | |a Amarillo, María E |e verfasserin |4 aut | |
| 700 | 1 | |a Pérez, Néstor G |e verfasserin |4 aut | |
| 700 | 1 | |a Díaz, Romina G |e verfasserin |4 aut | |
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