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

Melody Chemaly; Roisin McAllister; Aaron Peace; Anthony John Bjourson; Steve Watterson; Andrew Parton; Matthias Clauss; Victoria McGilligan

doi:10.1016/j.athplu.2022.09.001

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

Atheroscler Plus. 2022 Sep 28:50:40-49. doi: 10.1016/j.athplu.2022.09.001. eCollection 2022 Dec.

Authors

Melody Chemaly¹, Roisin McAllister², Aaron Peace^{2

3}, Anthony John Bjourson², Steve Watterson², Andrew Parton⁴, Matthias Clauss^{5

6}, Victoria McGilligan²

Affiliations

¹ Department of Molecular Medicine and Surgery, Karolinska Institute, SE-171 76 Solna, Sweden.
² Northern Ireland Centre for Stratified Medicine, School of Biomedical Sciences, Ulster University, Altnagelvin Hospital, Londonderry, BT47 6SB, Northern Ireland, UK.
³ Cardiology Department, Western Health and Social Care Trust, Altnagelvin Hospital, Glenshane Road, Londonderry, BT47 6SB, Northern Ireland, UK.
⁴ Ensembl Variation, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK.
⁵ Department of Cellular and Integrative Physiology, Indiana University, Indianapolis, IN, 46202, USA.
⁶ Centre for Molecular Bioscience, Ulster University, Coleraine, BT52 1SA, Northern Ireland, UK.

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.

Keywords: Acute coronary syndrome; Coronary artery disease; Major adverse cardiovascular events; Tumour necrosis factor alpha converting enzyme TACE/ADAM17.