Atherosclerosis results from maladaptive
inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque
necrosis, which underlies the instability that promotes plaque
rupture and
myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell
necrosis regulated by RIP3 and MLKL
kinases that, in contrast to apoptosis, induces a proinflammatory state. We show herein that necroptotic cell death is activated in human advanced
atherosclerotic plaques and can be targeted in experimental
atherosclerosis for both therapeutic and diagnostic interventions. In humans with unstable
carotid atherosclerosis, expression of RIP3 and MLKL is increased, and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced
atheromas. Investigation of the molecular mechanisms underlying necroptosis showed that atherogenic forms of
low-density lipoprotein increase RIP3 and MLKL transcription and phosphorylation-two critical steps in the execution of necroptosis. Using a radiotracer developed with the necroptosis inhibitor
necrostatin-1 (Nec-1), we show that (123)I-Nec-1 localizes specifically to
atherosclerotic plaques in
Apoe (-/-) mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of
Apoe (-/-) mice with established
atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Collectively, our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in
atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable
atherosclerosis.