Abstract
Cardiovascular diseases, including peripheral arterial and venous disease, myocardial infarction, and stroke, are the number one cause of death worldwide annually. In the last 20 years, the role of necroptosis, a newly identified form of regulated necrotic cell death, in cardiovascular disease has come to light. Specifically, the damaging role of two kinase proteins pivotal in the necroptosis pathway, Receptor Interacting Protein Kinase 1 (RIPK1) and Receptor Interacting Protein Kinase 3 (RIPK3), in cardiovascular disease has become a subject of great interest and importance. In this review, we provide an overview of the current evidence supporting a pathologic role of RIPK1 and RIPK3 in cardiovascular disease. Moreover, we highlight the evidence behind the efficacy of targeted RIPK1 and RIPK3 inhibitors in the prevention and treatment of cardiovascular disease.
Highlights
Introduction toRIP1 and RIPK3 and NecroptosisReceptor interacting serine/threonine–protein kinase 1 (RIPK1) and receptor interacting serine/threonine–protein kinase 3 (RIPK3) are intracellular signaling proteins known to play an important role in necroptosis
Overexpression with a phospholipid transfer protein (PLTP)-containing adenovirus vector increased RIPK3 protein levels detected in murine atherosclerotic plaques, lesion area and intra-lesion cell death [23]. These findings collectively suggest that necroptosis occurs in human atherosclerotic disease and that Receptor Interacting Protein Kinase 1 (RIPK1) and RIPK3 contribute to the atherosclerosis pathophysiology
While the effects of RIPK1 and RIPK3 are pleomorphic and include inducing local inflammation, the authors of this study showed no reduction in inflammatory cytokines in Nec-1 treated mice
Summary
Receptor interacting serine/threonine–protein kinase 1 (RIPK1) and receptor interacting serine/threonine–protein kinase 3 (RIPK3) are intracellular signaling proteins known to play an important role in necroptosis. While not characterized in the initial study, the authors suggested that the early stages of apoptosis and necrosis may share a common signaling pathway [4]. This theory has subsequently gone on to be validated. Complex IIb consists of activated, phosphorylated RIPK1 and RIPK3, which go on to phosphorylate the pseudokinase Mixed Lineage Kinase Domain like protein (MLKL), a key driver of necroptosis. The interactions between these pathways are complex, and the activation of one pathway can have a regulatory effect on signaling through the other pathway. Necroptosis is thought to play a role in cardiovascular diseases by causing cell death, and by driving inflammation and inflammasome activation
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