E3 Ubiquitin Ligases as Immunotherapeutic Target in Atherosclerotic Cardiovascular Disease

Kikkie Poels; Winnie G Vos; Esther Lutgens; Tom T P Seijkens

doi:10.3389/fcvm.2020.00106

E3 Ubiquitin Ligases as Immunotherapeutic Target in Atherosclerotic Cardiovascular Disease

Front Cardiovasc Med. 2020 Jun 5:7:106. doi: 10.3389/fcvm.2020.00106. eCollection 2020.

Authors

Kikkie Poels¹, Winnie G Vos¹, Esther Lutgens^{1

2

3}, Tom T P Seijkens^{1

4

5}

Affiliations

¹ Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, Netherlands.
² Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany.
³ German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
⁴ Department of Internal Medicine, Amsterdam UMC, Location VUmc, VU University, Amsterdam, Netherlands.
⁵ Department of Hematology, Amsterdam UMC, Location VUmc, VU University, Amsterdam, Netherlands.

Abstract

Chronic low-grade inflammation drives atherosclerosis and despite optimal pharmacological treatment of classical cardiovascular risk factors, one third of the patients with atherosclerotic cardiovascular disease has elevated inflammatory biomarkers. Additional anti-inflammatory strategies to target this residual inflammatory cardiovascular risk are therefore required. T-cells are a dominant cell type in human atherosclerotic lesions. Modulation of T-cell activation is therefore a potential strategy to target inflammation in atherosclerosis. Ubiquitination is an important regulatory mechanism of T-cell activation and several E3 ubiquitin ligases, including casitas B-lineage lymphoma proto-oncogene B (Cbl-B), itchy homolog (Itch), and gene related to anergy in lymphocytes (GRAIL), function as a natural brake on T-cell activation. In this review we discuss recent insights on the role of Cbl-B, Itch, and GRAIL in atherosclerosis and explore the therapeutic potential of these E3 ubiquitin ligases in cardiovascular medicine.

Keywords: Cbl-B; E3 ubiquitin ligases; GRAIL; Itch; atherosclerosis; inflammation.

Publication types

Review