Browsing by Author "McGilligan, Victoria"

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    Role of tumour necrosis factor alpha converting enzyme (TACE/ADAM17) and associated proteins in coronary artery disease and cardiac events
    (Elsevier, 2017) Chemaly, Melody; McGilligan, Victoria; Gibson, Mark; Clauss, Matthias; Watterson, Steven; Alexander, H. Denis; Bjourson, Anthony John; Peace, Aaron; Medicine, School of Medicine
    Tumour necrosis factor alpha converting enzyme (TACE/ADAM17) is a member of the A disintegrin and metalloproteinase (ADAM) family of ectodomain shedding proteinases. It regulates many inflammatory processes by cleaving several transmembrane proteins, including tumour necrosis factor alpha (TNFα) and its receptors tumour necrosis factor alpha receptor 1 and tumour necrosis factor alpha receptor 2. There is evidence that TACE is involved in several inflammatory diseases, such as ischaemia, heart failure, arthritis, atherosclerosis, diabetes and cancer as well as neurological and immune diseases. This review summarizes the latest discoveries regarding the mechanism of action and regulation of TACE. It also focuses on the role of TACE in atherosclerosis and coronary artery disease (CAD), highlighting clinical studies that have investigated its expression and protein activity. The multitude of substrates cleaved by TACE make this enzyme an attractive target for therapy and a candidate for biomarker research and development in CAD.
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    TACE/ADAM17 substrates associate with ACS (Ep-CAM, HB-EGF) and follow-up MACE (TNFR1 and TNFR2)
    (Elsevier, 2022-09-28) Chemaly, Melody; McAllister, Roisin; Peace, Aaron; Bjourson, Anthony John; Watterson, Steve; Parton, Andrew; Clauss, Matthias; McGilligan, Victoria; Cellular and Integrative Physiology, School of Medicine
    Background and aims: TACE/ADAM17 is a membrane bound metalloprotease, which cleaves substrates involved in immune and inflammatory responses and plays a role in coronary artery disease (CAD). We measured TACE and its substrates in CAD patients to identify potential biomarkers within this molecular pathway with potential for acute coronary syndrome (ACS) and major adverse cardiovascular events (MACE) prediction. Methods: Blood samples were obtained from consecutive patients (n = 229) with coronary angiographic evidence of CAD admitted with ACS or electively. MACE were recorded after a median 3-year follow-up. Controls (n = 115) had a <10% CAD risk as per the HeartSCORE. TACE and TIMP3 protein and mRNA levels were measured by ELISA and RT-qPCR respectively. TACE substrates were measured using a multiplex proximity extension assay. Results: TACE mRNA and cell protein levels (p < 0.01) and TACE substrates LDLR (p = 0.006), TRANCE (p = 0.045), LAG-3 (p < 0.001) and ACE2 (p < 0.001) plasma levels were significantly higher in CAD patients versus controls. TACE inhibitor TIMP3 mRNA levels were significantly lower in CAD patients and tended to be lower in the ACS population (p < 0.05). TACE substrates TNFR1 (OR:3.237,CI:1.514-6.923,p = 0.002), HB-EGF (OR:0.484,CI:0.288-0.813,p = 0.006) and Ep-CAM (OR:0.555,CI:0.327-0.829,p = 0.004) accurately classified ACS patients with HB-EGF and Ep-CAM levels being lower compared to electively admitted patients. TNFR1 (OR:2.317,CI:1.377-3.898,p = 0.002) and TNFR2 (OR:1.902,CI:1.072-3.373,p = 0.028) were significantly higher on admission in those patients who developed MACE within 3 years. Conclusions: We demonstrate a possible role of TACE substrates LAG-3, HB-EGF and Ep-CAM in atherosclerotic plaque development and stability. We also underline the importance of measuring TNFR1 and TNFR2 earlier than previously appreciated for MACE prediction. We report an important role of TIMP3 in regulating TACE levels.