Biology subjects

Mills, N. L.

Publications and source records attributed to Mills, N. L..

3 recordsLinked to original sources

bioRxiv2024

Pharmacological inhibition of 11βhydroxysteroid dehydrogenase type 1 after myocardial infarction targets extracellular matrix processing and preserves cardiac function in a translational mini-pig model

Background and PurposePlasma glucocorticoids (GCs) increase acutely after myocardial infarction (MI), thereafter tissue levels are amplified selectively within cells expressing 11{beta}Hydroxysteroid Dehydrogenase type 1 (11{beta}HSD1) that regenerates active GCs from circulating metabolites. GCs 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 11{beta}HSD1 inhibition after MI to prevent deterioration of cardiac function and its impact on wound repair. Experimental ApproachAdult female Gottingen mini-pigs underwent percutaneous balloon MI/reperfusion and were randomised to receive either oral 11{beta}HSD1 inhibitor AZD8329 (n=11), or vehicle (n=9), from 2 until 27 days later, with concurrent administration of clinically relevant therapeutic intervention (anti-platelet, statin and ACE inhibitor). Key ResultsAZD8329 treatment increased plasma accumulation of cortisone substrate consistent with successful 11{beta}HSD1 inhibition. Gadolinium-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 11{beta}HSD1 inhibitor on neovascularisation or infarct area. Mass spectrometry imaging revealed AZD8329 binding to the healing infarct and altered regulation of extracellular matrix (ECM) processing was highlighted by birefringence microscopy and proteomic analysis. Conclusions and ImplicationsPharmacological inhibition of 11{beta}HSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11{beta}HSD1 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. Bullet Point Summary What is already known?O_LIGCs are released from the adrenal gland after MI, but also regenerated within the heart from circulating precursors by the enzyme 11{beta}HSD1 in cardiomyocytes, fibroblasts and macrophages. C_LIO_LIGenetic suppression of Hsd11b1 expression in the mouse promotes neovascularisation, prevents infarct expansion during infarct repair after MI and the development of heart failure. C_LI What does this study add?O_LIOral pharmacological inhibition of 11{beta}HSD1 after MI/reperfusion in a translational mini-pig model of MI receiving concurrent clinically relevant therapy prevents cardiac functional deterioration and adverse ventricular remodelling over the following 4 weeks. C_LIO_LIMass spectrometry imaging reveals target engagement of the 11{beta}HSD1i in the repairing infarct. C_LIO_LIThe mechanism is independent of neovascularisation but does involve modification of extracellular matrix remodelling during repair and scar formation. C_LI What is the clinical significance?O_LITissue 11{beta}HSD1 expression is increased in aging when the risk of MI is higher. C_LIO_LIPharmacological inhibitors of 11{beta}HSD1 have safely reached phase 2 clinical trials for dementia and metabolic disease and could be repurposed for use post-MI to prevent the development of heart failure. C_LI

pharmacology and toxicology↗

bioRxiv2023

Cell-autonomous metabolic reprogramming and oxidative stress underlie endothelial dysfunction in acute myocardial infarction

Compelling evidence has accumulated for the role of oxidative stress on the endothelial cell (EC) dysfunction underlying acute coronary syndromes. However, understanding the metabolic determinants of EC dysfunction has been hampered by the scarcity of appropriate cell models. Here, we have generated and phenotypically characterized EC derived from thrombectomy specimens in patients with acute myocardial infarction (AMI). We have found that AMI-derived endothelial cells (AMIECs), but not control EC from health coronary arteries, display impaired growth, migration and tubulogenesis. These phenotypic abnormalities were accompanied with metabolic abnormalities including augmentation of reactive oxygen species (ROS) and glutathione intracellular content, along with diminished glucose consumption coupled to increased lactate production. In AMIECs, the protein levels of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase type 3, PFKFB3, were downregulated, while those of PFKFB4 were upregulated, suggesting a shunting of glycolysis towards the pentose phosphate pathway (PPP) in the pathological ECs. PPP overactivation was further supported by upregulation of G6PD in AMIECs, the key enzyme in the oxidative branch of the PPP, which supplies the bulk of NADPH reducing equivalents necessary for the reduction/turnover and lipid synthesis.. Further, the glutaminolytic enzyme glutaminase (GLS) was upregulated in AMIECs, providing a mechanistic explanation for the observed increase in glutathione content. Finally, AMIECs had higher mitochondrial membrane potential than control ECs, which, together with high ROS levels, suggest a highly coupled mitochondrial activity in patient ECs. We suggest that high proton coupling underlies the abnormally high production of ROS, balanced by PPP-driven glutathione turnover, as a primary, cell-autonomous abnormality driving EC dysfunction in AMI.

cell biology↗

bioRxiv2018

Global Adoption of High-Sensitivity Cardiac Troponins and the Universal Definition of Myocardial Infarction

ImportanceThe third Universal Definition of Myocardial Infarction aimed to standardize the approach to the diagnosis and management of myocardial infarction. High-sensitivity cardiac troponin testing was recommended, as these assays have improved precision at low concentrations, but concerns over specificity may have limited implementation.\n\nObjectiveTo determine the global adoption of high-sensitivity cardiac troponin assays and key recommendations from the Universal Definition.\n\nDesign, Setting and ParticipantsGlobal survey of 1,902 medical centers across 23 countries evenly distributed across all five continents. Included respondents were involved in the diagnosis and management of patients with suspected acute coronary syndrome at their institutions.\n\nMain Outcomes and MeasuresStructured questionnaire detailing the primary biomarker used for myocardial infarction, diagnostic thresholds and critical elements of clinical pathways for comparison to the third Universal Definition recommendations.\n\nResultsCardiac troponin was the primary diagnostic biomarker for myocardial infarction at 96% of all sites surveyed. Only 41% of centers had adopted high-sensitivity cardiac troponin assays, with wide variation from 7% in North America to 60% in Europe. Sites using high-sensitivity assays more frequently employed serial sampling pathways (91% vs. 78%) and the 99th percentile diagnostic threshold (74% vs. 66%) when compared to sites using the previous generation of troponin assays. Furthermore, sites using high-sensitivity assays more often used earlier serial sampling ([≤]3 hours) and accelerated diagnostic pathways. However, fewer than 1 in 5 sites using high-sensitivity assays had adopted sex-specific thresholds (18%).\n\nConclusions and RelevanceProgress has been made in adopting the recommendations of the Universal Definition of Myocardial Infarction, particularly in the use of the 99th percentile diagnostic threshold and serial sampling. However, high-sensitivity assays are used in a minority of sites and sex-specific thresholds in even fewer. These findings highlight regions where additional efforts are required to improve the risk stratification and diagnosis of patients with myocardial infarction.

biochemistry↗