Journal of Inflammation Research (Oct 2021)
New Horizons for the Roles and Association of APE1/Ref-1 and ABCA1 in Atherosclerosis
Abstract
Wujun Chen,1 Shuai Wang,2 Dongming Xing1,3 1Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, 266071, People’s Republic of China; 2School of Medical Imaging, Radiotherapy Department of Affiliated Hospital, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of China; 3School of Life Sciences, Tsinghua University, Beijing, 100084, People’s Republic of ChinaCorrespondence: Dongming XingCancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, People’s Republic of ChinaTel +86-532- 82991017Email [email protected] WangSchool of Medical Imaging, Radiotherapy Department of Affiliated Hospital, Weifang Medical University, Weifang, Shandong, People’s Republic of ChinaTel +86-536-8462228Email [email protected]: Atherosclerosis is the leading cause of death worldwide. APE1/Ref-1 and ABCA1 play key roles in the progression of atherosclerosis. APE1/Ref-1 suppresses atherosclerosis via multiple mechanisms, including reducing the IL-6-, TNF-α-, and IL-1β-mediated proinflammatory responses, suppressing ROS-mediated oxidant activity and Bax/Bcl-2-mediated vascular calcification and apoptosis, and reducing LOX-1-mediated cholesterol uptake. However, APE1/Ref-1 also promotes atherosclerosis by increasing the activity of the NK-κB and S1PR1 pathways. APE1/Ref-1 localizes to the nucleus, cytoplasm, and mitochondria and can be secreted from the cell. APE1/Ref-1 localization is dynamically regulated by the disease state and may be responsible for its proatherogenic and antiatherogenic effects. ABCA1 promotes cholesterol efflux and anti-inflammatory responses by binding to apoA-I and regulates apoptotic cell clearance and HSPC proliferation to protect against inflammatory responses. Interestingly, in addition to mediating these functions, ABCA1 promotes the secretion of acetylated APE1/Ref-1 (AcAPE1/Ref-1), a therapeutic target, which protects against atherosclerosis development. The APE1/Ref-1 inhibitor APX3330 is being evaluated in a phase II clinical trial. The LXR agonist LXR-623 (WAY-252623) is an agonist of ABCA1 and the first LXR-targeting compound to be evaluated in clinical trials. In this article, we review the roles of ABCA1 and APE1/Ref-1 in atherosclerosis and focus on new insights into the ABCA1-APE1/Ref-1 axis and its potential as a novel therapeutic target in atherosclerosis.Keywords: atherosclerosis, inflammatory, APE1/Ref-1, ABCA1, cholesterol efflux
