SFEBES2023 Oral Communications Adrenal and Cardiovascular (6 abstracts)
11βHSD1 inhibition improves cardiac function compared to standard therapy in a translational pig mode through regulation of extracellular matrix
Sara Al Disi 1 , Raimondo Ascione 2 , Tom Johnson 2 , Eva Sammut 2 , Vito Domenico Bruno 2 , Shazia Khan 1 , Trisha Singh 1 , Daniel Baz Lopez 2 , Carol-Ann James 2 , Brian Walker 1 , Nicholas Mills 1 , Scott Webster 1 , Adrian Freeman 3 , Andrew Whittaker 3 , Ruth Andrew 1 & Gillian Gray 1
1University of Edinburgh, Edinburgh, United Kingdom. 2University of Brisol, Bristol, United Kingdom. 3AstraZeneca, Cambridge, United Kingdom
Glucocorticoids (GCs) protect cardiomyocytes immediately after myocardial infarction (MI), but GCs subsequently regenerated within the heart by 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) are detrimental during infarct repair, with functional outcomes post-MI improved in mice lacking 11βHSD1. Pharmacological 11βHSD1 inhibition (AZD8329 50mg/kg, 11βHSD1i) was compared to standard clinical therapy (SCT) in a translational pig model (female, 11βHSD1i n =11 vs SCT n =9). MI was induced in Goettingen mini-pigs by temporary coronary occlusion followed by reperfusion, and magnetic resonance imaging was conducted. Fresh frozen tissue and fixed cross-sections of left ventricle were collected, with ethical approval, 28d after MI. Although scar size did not differ between groups, ejection fraction was improved 28d post-MI in 11βHSD1i compared to SCT (P<0.05). Mass spectrometry imaging on frozen sections (12 µm) identified 11βHSD1i in infarct scars of 11βHSD1i-treated pigs, aligning with immunostaining for activated fibroblasts. Proteomic analysis of border zone (BZ) tissue highlighted extracellular matrix (ECM) organisation (FDR-corrected P*<0.05) as main pathways modified by 11βHSD1i vs SC, showing collagen processing enzymes (P4HA2, PCOLCE, P*<0.05) and ECM proteins (FN1, VTN, LTBP1, MATN4, P*<0.05) were downregulated in the BZ by 11βHSD1i vs SCT. Collagen processing enzyme lysyl oxidase’s mRNA expression was also reduced in the BZ of 11βHSD1i-treated pigs, relative to SCT (P<0.05). While total infarct collagen (picrosirius red) and transcript abundance (qPCR) of Collagen I or III did not differ between groups, polarised light microscopy revealed a trend for decreased thick collagen in scars of 11βHSD1i-treated pigs. Finally, brain natriuretic peptide, marking heart failure, was reduced in BZ (P*=0.05), and collagen I (P=0.05) was downregulated in the remote myocardium of 11βHSD1i-treated pigs, consistent with reduced wall stress. These data provide the first evidence of 11βHSD1i cardiac protection in a translational model, and support a role of fibroblasts and alteration of collagen processing as the mechanism underlying this effect.
Volume 94
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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