TACE/ADAM17 substrates associate with ACS (Ep-CAM, HB-EGF) and follow-up MACE (TNFR1 and TNFR2)

Melody Chemaly, Roisin McAllister, Aaron Peace, AJ Bjourson, Steven Watterson, Andrew Parton, Matthias Clauss, V. E. McGilligan

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Abstract

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.

Original languageEnglish
Pages (from-to)40-49
Number of pages10
JournalAtherosclerosis plus
Volume50
Early online date28 Sep 2022
DOIs
Publication statusPublished (in print/issue) - 31 Dec 2022

Bibliographical note

Funding Information:
This work was supported by grant of £11.5 M awarded to A. J. B. from the European Union Regional Development Fund European Union Sustainable Competitiveness Programme for Northern Ireland; Northern Ireland Public Health Agency (Health and Social Care Research and Development Division) and the University of Ulster and the Department of Employment and Learning in Northern Ireland.

Publisher Copyright:
© 2022 The Authors

Keywords

  • Coronary artery disease
  • Tumour necrosis factor alpha converting enzyme TACE/ADAM17
  • Major adverse cardiovascular events
  • Acute coronary syndrome

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