Dataset Information

Pharmacological inhibition of the glucocorticoid regenerating enzyme 11ßhydroxysteroid dehydrogenase type 1 after myocardial infarction preserves cardiac function in a translational pig model

ABSTRACT: Background and Purpose: Adrenal glucocorticoids (GC) increase acutely after myocardial infarction (MI) and thereafter tissue levels are maintained selectively within cells expressing the enzyme 11ßHydroxysteroid Dehydrogenase type 1 (11ßHSD1) that regenerates active GC from circulating metabolites. GC initially protect cardiomyocytes and prevent excessive inflammation after MI but can also suppress subsequent wound repair leading to functional decline. The present study aimed to investigate the potential of pharmacological 11ßHSD1inhibition after MI to prevent deterioration of cardiac function. Experimental Approach: Oral 11ßHSD1 inhibitor AZD8329, or vehicle, were administered from 48h to 28 days after ischaemia/reperfusion in a translational pig model concurrently receiving clinically relevant therapeutic intervention (statin, anti-platelet, ACE inhibitor and ß adrenoreceptor antagonist). Key Results: AZD8329 treatment resulted in increased plasma accumulation of cortisone substrate consistent with successful 11ßHSD1 inhibition. Gd enhanced MRI showed equivalent infarct size in both groups prior to commencing treatment. 28 days after MI cardiac function and LV area were preserved in the AZD8329 treated group relative to vehicle. There was no impact of 11ßHSD1 inhibitor on neovascularisation or infarct area compared to vehicle. However, 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 11ßHSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11ßHSD1 inhibitors have safely reached phase 2 in clinical trials and could be repurposed for use after MI/reperfusion to prevent the development of heart failure.

INSTRUMENT(S):

ORGANISM(S): Sus Scrofa Domesticus (domestic Pig)

TISSUE(S): Blood Serum, Blood

SUBMITTER: Alex von Kriegsheim

LAB HEAD: Gillian Gray

PROVIDER: PXD055401 | Pride | 2026-01-15

REPOSITORIES: Pride

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			Action	DRS
	20230202-HeartTissue10-03_01.raw	Raw
	20230202-HeartTissue13-04_01.raw	Raw
	20230202-HeartTissue16-05_01.raw	Raw
	20230202-HeartTissue18-06_01.raw	Raw
	20230202-HeartTissue19-07_01.raw	Raw

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Publications

Pharmacological inhibition of hydroxysteroid 11-beta dehydrogenase type 1 (11-βHSD1) after myocardial infarction preserves cardiac function in a translational mini-pig model.

Al Disi Sara S Ascione Raimondo R Khan Shazia S Johnson Thomas T Sammut Eva E Bruno Vito Domenico VD Baz Lopez Daniel D James Carol-Anne CA Simpson Joanna J Homer Natalie Z NZ Millar Michael M Singh Trisha T von Kreigsheim Alex A Mills Nick L NL Walker Brian R BR Andrew Ruth R Webster Scott P SP Whittaker Andrew A Freeman Adrian A Gray Gillian A GA

British journal of pharmacology 20251228

<h4>Background and purpose</h4>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 deteriora ...[more]

PMID: 41456844

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Project description:Ischemic heart failure after acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. We recently reported that activation of a trans-valvular axial-flow pump in the LV and delaying myocardial reperfusion, known as Primary Unloading, limits infarct size by reducing LV wall stress and increasing expression of the cardioprotective cytokine, stromal derived factor 1 alpha (SDF1a). The mechanisms underlying the cardioprotective benefit and sustained effect of Primary Unloading remain poorly understood. We now tested the importance of delayed reperfusion, the functional significance of SDF1a, and the late-term impact on myocardial function and scar size associated with Primary Unloading. Adult male swine were subjected to Primary Reperfusion or Primary Unloading after 90 minutes of left anterior descending artery occlusion. Compared to Primary Reperfusion, 30 minutes of Primary Unloading was necessary and sufficient prior to reperfusion to limit infarct size. Primary Unloading was associated with a global shift in gene expression within the infarct zone favoring cardioprotection. Compared to Primary Reperfusion, Primary Unloading for 30 minutes preserved SDF1a protein levels without changing SDF1a mRNA levels within the infarct zone and further promoted a shift towards anti-apoptotic signaling within the infarct zone. Primary Unloading reduced activity levels of proteases known to degrade SDF1a and blocking the SDF1a receptor, CXCR4, attenuated the cardioprotective effect of Primary Unloading. Primary Unloading further reduced LV scar size, improved cardiac function, limited expression of markers associated with heart failure and maladaptive remodeling within the non-infarct zone 28 days after acute myocardial infarction. In conclusion, we introduce that Primary Unloading for 30 minutes before, not after reperfusion limits infarct size, increases SDF1a levels within the infarct zone, and results in a durable reduction in LV scar size, improved cardiac function, and limits markers of heart failure and maladaptive remodeling 28 days after AMI.