Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis

ABSTRACT

Introduction: Formation and enlargement of a necrotic core play a pivotal role in atherogenesis. Since the discovery of necroptosis, which is a regulated form of necrosis, prevention of necrotic cell death has become an attractive therapeutic goal to reduce plaque formation.

Areas covered: This review highlights the triggers and consequences of (unregulated) necrosis and necroptosis in atherosclerosis. The authors discuss different pharmacological strategies to inhibit necrotic cell death in advanced atherosclerotic plaques.

Expert opinion: Addition of a necrosis or necroptosis inhibitor to standard statin therapy could be a promising strategy for primary prevention of cardiovascular disease. However, a necrosis inhibitor cannot block all necrosis stimuli in atherosclerotic plaques. A necroptosis inhibitor could be more effective, because necroptosis is mediated by specific proteins, termed receptor-interacting serine/threonine-protein kinases (RIPK) and mixed lineage kinase domain-like pseudokinase (MLKL). Currently, only RIPK1 inhibitors have been successfully used in atherosclerotic mouse models to inhibit necroptosis. However, because RIPK1 is involved in both necroptosis and apoptosis, and also RIPK1-independent necroptosis can occur, we feel that targeting RIPK3 and MLKL could be a more attractive therapeutic approach to inhibit necroptosis. Therefore, future challenges will consist of developing RIPK3 and MLKL inhibitors applicable in both preclinical and clinical settings.

KEYWORDS:

• Atherosclerosis
• necroptosis
• necrosis
• necrosis inhibitors
• RIPK1 inhibitors
• RIPK3 inhibitors
• MLKL inhibitors

Highlights

• Formation and enlargement of the necrotic core play a significant role in the pathology of unstable atherosclerotic plaque.

• Necrotic cell death in an atherosclerotic plaque can be induced by several stimuli including oxLDL, ROS accumulation, intracellular Ca²⁺ overload and defective efferocytosis, thereby promoting plaque inflammation and plaque vulnerability.

• Necroptosis has been recently identified as a form of regulated necrosis, which is characterized by the formation of a pro-necrotic complex consisting of RIPK1 and RIPK3.

• The necroptosis mediators RIPK1 and RIPK3 play a key role in the development of atherosclerotic plaques.

• The combination of a necroptosis inhibitor with standard statin therapy could be an attractive alternative therapeutic approach for primary prevention of cardiovascular diseases.

• Because RIPK1 plays a role in necroptosis as well as in apoptosis, and necroptosis can also occur in a RIPK1-independent manner, the downstream mediators RIPK3 and MLKL are more interesting targets to inhibit necroptosis.

Acknowledgments

The authors are grateful to Dr. Bronwen Martin for critical reading of the manuscript.

Declaration of Interest

I Coornaert is a fellow of the Fund for Scientific Research (FWO)-Flanders. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Fund for Scientific Research (FWO)-Flanders (EOS 30826052) and the University of Antwerp (BOF).