Abstract
Background and Purpose:
Plasma glucocorticoids increase acutely after MI, thereafter tissue levels are amplified selectively within cells expressing 11-ßhydroxysteroid dehydrogenase type 1 (11-ßHSD1) that regenerates active glucocorticoids from circulating metabolites. Glucocorticoids initially protect cardiomyocytes and prevent excessive inflammation after MI but can also suppress wound repair leading to functional decline. We investigate 11-ßHSD1 inhibition after MI to prevent deterioration of cardiac function and its impact on wound repair.
Experimental Approach:
Adult female Gottingen mini-pigs underwent percutaneous balloon MI/reperfusion and were randomised to receive either oral 11-ßHSD1 inhibitor AZD8329 (n = 11) or vehicle (n = 9), from 2 until 27 days later, with concurrent administration of relevant therapeutic intervention (anti-platelet, statin and ACE inhibitor).
Key Results:
AZD8329 treatment increased plasma accumulation of cortisone substrate showing successful 11-ßHSD1 inhibition. Gadolinium-enhanced magnetic resonance imaging (MRI) showed equivalent infarct size in both groups prior to commencing treatment. Twenty-eight days after MI cardiac function and left ventricle area were preserved in the AZD8329 treated group relative to vehicle. There was no impact of 11-ßHSD1 inhibitor on neovascularisation or infarct area. Mass spectrometry imaging revealed AZD8329 binding to the healing infarct and altered regulation of extracellular matrix processing was highlighted by birefringence microscopy and proteomic analysis.
Conclusions and Implications:
Pharmacological inhibition of 11-ßHSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11-ßHSD1 inhibitors have safely reached Phase 2 clinical trials in diabetes and dementia, and could be repurposed as an addition to standard care after MI to prevent the development of heart failure.
Plasma glucocorticoids increase acutely after MI, thereafter tissue levels are amplified selectively within cells expressing 11-ßhydroxysteroid dehydrogenase type 1 (11-ßHSD1) that regenerates active glucocorticoids from circulating metabolites. Glucocorticoids initially protect cardiomyocytes and prevent excessive inflammation after MI but can also suppress wound repair leading to functional decline. We investigate 11-ßHSD1 inhibition after MI to prevent deterioration of cardiac function and its impact on wound repair.
Experimental Approach:
Adult female Gottingen mini-pigs underwent percutaneous balloon MI/reperfusion and were randomised to receive either oral 11-ßHSD1 inhibitor AZD8329 (n = 11) or vehicle (n = 9), from 2 until 27 days later, with concurrent administration of relevant therapeutic intervention (anti-platelet, statin and ACE inhibitor).
Key Results:
AZD8329 treatment increased plasma accumulation of cortisone substrate showing successful 11-ßHSD1 inhibition. Gadolinium-enhanced magnetic resonance imaging (MRI) showed equivalent infarct size in both groups prior to commencing treatment. Twenty-eight days after MI cardiac function and left ventricle area were preserved in the AZD8329 treated group relative to vehicle. There was no impact of 11-ßHSD1 inhibitor on neovascularisation or infarct area. Mass spectrometry imaging revealed AZD8329 binding to the healing infarct and altered regulation of extracellular matrix processing was highlighted by birefringence microscopy and proteomic analysis.
Conclusions and Implications:
Pharmacological inhibition of 11-ßHSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11-ßHSD1 inhibitors have safely reached Phase 2 clinical trials in diabetes and dementia, and could be repurposed as an addition to standard care after MI to prevent the development of heart failure.
| Original language | English |
|---|---|
| Number of pages | 20 |
| Journal | British Journal of Pharmacology |
| Early online date | 28 Dec 2025 |
| DOIs | |
| Publication status | E-pub ahead of print - 28 Dec 2025 |
Bibliographical note
Publisher Copyright:© 2025 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
