Premium
Targeting macrophage necroptosis for therapeutic and diagnostic interventions to treat atherosclerosis
Author(s) -
Karunakaran Denuja,
Geoffrion Michele,
Wei Lihui,
Gan Wei,
Perisic Ljubica,
Maegdefessel Lars,
Hedin Ulf,
Sad Subash,
Virmani Renu,
Ruddy Terrence,
Rayner Katey
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.444.6
Subject(s) - necroptosis , programmed cell death , inflammation , apoptosis , cancer research , lesion , macrophage , necrosis , microbiology and biotechnology , pathogenesis , tumor necrosis factor alpha , biology , immunology , pathology , medicine , in vitro , biochemistry
Atherosclerosis is a disease of maladaptive inflammation driven primarily by macrophages, and as the atherosclerotic plaque progresses and becomes more complex, a necrotic core forms that ultimately underlies the instability that drives plaque rupture and myocardial infarction. Necroptosis or ‘programmed necrosis’ is an emerging cell death pathway involving kinases RIP3 and MLKL that in contrast to apoptosis, induces a pro‐inflammatory state. We hypothesize that macrophages undergo necroptosis in response to atherogenic stimuli in the vessel wall, and this process underlies necrotic core formation and plaque instability. Here, we show that oxidized LDL (oxLDL) induces necroptotic cell death in macrophages, which can be blocked by Nec‐1, a necroptosis inhibitor. Macrophages treated with oxidized LDL have increased expression of necroptotic genes RIP3 and MLKL through activation of the promoter region and increased RIP3 and MLKL phosphorylation‐ critical steps in the execution of necroptosis. Further, the combined treatment with oxLDL and DAMPs (damage associated molecular patterns) amplified macrophage necroptotic cell death, indicating that additional inflammatory stimuli present in the lesion could act synergistically to promote necroptosis. In a model of established atherosclerosis, Nec‐1 intervention in Apoe −/− mice reduced lesion size (p<0.05) and markers of plaque instability, including reduced necrotic core formation (62.6% reduction, p<0.01). Further, we developed a novel 123 I‐Nec‐1 radiotracer targeting the necroptosis pathway and show that it specifically localizes to and tightly correlates with atherosclerotic lesions. Lastly, in humans with unstable carotid atherosclerosis, expression of the necroptotic genes RIP3 and MLKL is elevated and MLKL phosphorylation is detected in advanced atheromas, indicating that the necroptotic pathway is highly activated in vulnerable plaques. In conclusion , our findings offer molecular insight into the mechanisms by which inflammatory atherogenic ligands drives cell death necrotic core formation that underlies unstable atherosclerosis and identify innovative diagnostic and therapeutic tools to treat atherosclerosis.