scholarly journals Macrophage autophagy regulates mitochondria‐mediated apoptosis and inhibits necrotic core formation in vulnerable plaques

2020 ◽  
Vol 24 (1) ◽  
pp. 260-275 ◽  
Author(s):  
Qingqing Xiao ◽  
Xinyu Che ◽  
Bin Cai ◽  
Zhenyu Tao ◽  
Hengyuan Zhang ◽  
...  
Keyword(s):  
Necrotic Core ◽  
Core Formation ◽  
Vulnerable Plaques

scholarly journals K-80003 Inhibition of Macrophage Apoptosis and Necrotic Core Development in Atherosclerotic Vulnerable Plaques

2021 ◽  
Author(s):  
Xiaolei Wang ◽  
Zhe Sun ◽  
Ruosen Yuan ◽  
Weifeng Zhang ◽  
Yejiao Shen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Necrotic Core ◽  
Control Group ◽  
Autophagic Flux ◽  
Plaque Progression ◽  
Core Formation ◽  
Vulnerable Plaques ◽  
Macrophage Apoptosis ◽  
Cellular Apoptosis

Abstract Purpose Macrophage apoptosis coupled with a defective phagocytic clearance of the apoptotic cells promotes plaque necrosis in advanced atherosclerosis, which causes acute atherothrombotic vascular disease. Nonsteroidal anti-inflammatory drug sulindac derivative K-80003 treatment was previously reported to dramatically attenuate atherosclerotic plaque progression and destabilization. However, the underlying mechanisms are not fully understood. This study aimed to determine the role of K-80003 on macrophage apoptosis and elucidate the underlying mechanism. Methods The mouse model of vulnerable carotid plaque in ApoE−/− mice was developed in vivo. Consequently, mice were randomly grouped into two study groups: the control group and the K-80003 group (30 mg/kg/day). Samples of carotid arteries were collected to determine atherosclerotic necrotic core area, cellular apoptosis, and oxidative stress. The effects of K-80003 on RAW264.7 macrophage apoptosis, oxidative stress, and autophagic flux were also examined in vitro. Results K-80003 significantly suppressed necrotic core formation and inhibited cellular apoptosis of vulnerable plaques. K-80003 can also inhibit 7-ketocholesterol-induced macrophage apoptosis in vitro. Furthermore, K-80003 inhibited intraplaque cellular apoptosis mainly through the suppression of oxidative stress, which is a key cause of advanced lesional macrophage apoptosis. Mechanistically, K-80003 prevented 7-ketocholesterol-induced impairment of autophagic flux in macrophages, evidenced by the decreased LC3II and SQSTM1/p62 expression, GFP-RFP-LC3 cancellation upon K-80003 treatment. Conclusion Inhibition of macrophage apoptosis and necrotic core formation by autophagy-mediated reduction of oxidative stress is one mechanism of the suppression of plaque progression and destabilization by K-80003.

scholarly journals Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis

2016 ◽  
Vol 2 (7) ◽  
pp. e1600224 ◽  
Author(s):  
Denuja Karunakaran ◽  
Michele Geoffrion ◽  
Lihui Wei ◽  
Wei Gan ◽  
Laura Richards ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Density Lipoprotein ◽  
Necrotic Core ◽  
Atherosclerotic Plaques ◽  
Core Formation ◽  
Macrophage Cell ◽  
Plaque Instability

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 123I-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.

scholarly journals Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap ThicknessHighlights

2017 ◽  
Vol 37 (12) ◽  
pp. 2322-2332 ◽  
Author(s):  
Emma P.K. Yu ◽  
Johannes Reinhold ◽  
Haixiang Yu ◽  
Lakshi Starks ◽  
Anna K. Uryga ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Necrotic Core ◽  
Core Formation ◽  
Fibrous Cap

Abstract 3: Targeting Macrophage Necroptosis for Therapeutic and Diagnostic Interventions to Treat Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Denuja Karunakaran ◽  
Michele Geoffrion ◽  
Lihui Wei ◽  
Wei Gan ◽  
Ljubica Perisic ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Oxidized Ldl ◽  
Combined Treatment ◽  
Necrotic Core ◽  
Core Formation ◽  
Macrophage Cell ◽  
Plaque Instability

Background: 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. As such, 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 pro-inflammatory state. We hypothesize that atherogenic ligands within the plaque promote macrophage necroptosis and this process underlies necrotic core formation and drives atherosclerotic plaque instability. Results: 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 plaque necroptosis showed that macrophages treated with oxidized LDL have increased expression of necroptotic genes RIP3 and MLKL through ROS-dependent activation of the promoter region and increased RIP3 and MLKL phosphorylation. 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. Using a radiotracer developed with the necroptosis inhibitor Nec-1, we show that 123 I-Nec1 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. Conclusions: 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.

scholarly journals Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions

2006 ◽  
Vol 3 (4) ◽  
pp. 257-266 ◽  
Author(s):  
Seongah Han ◽  
Chien-Ping Liang ◽  
Tracie DeVries-Seimon ◽  
Mollie Ranalletta ◽  
Carrie L. Welch ◽  
...  
Keyword(s):  
Er Stress ◽  
Insulin Receptor ◽  
Necrotic Core ◽  
Core Formation ◽  
Atherosclerotic Lesions ◽  
Induced Apoptosis

Influence of Plaque Geometry on Peak Cap Stresses

2011 ◽  
Author(s):  
A. C. Akyildiz ◽  
L. Speelman ◽  
H. Nieuwstadt ◽  
J. Wentzel ◽  
A. van der Steen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Coronary Artery ◽  
Vulnerable Plaque ◽  
Necrotic Core ◽  
Myocardial Infarctions ◽  
Vulnerable Plaques

Atherosclerosis is an important cardiovascular disease in which plaque build up occurs in vessels. Plaques with thin cap and thick necrotic core are defined as vulnerable plaques. Rupture of the cap of a vulnerable plaque in a coronary artery is the underlying cause of the majority of acute myocardial infarctions and sudden coronary deaths [1].

scholarly journals Loss of MLKL Decreases Necrotic Core but Increases Macrophage Lipid Accumulation In Atherosclerosis

2019 ◽  
Author(s):  
Adil Rasheed ◽  
Sabrina Robichaud ◽  
My-Anh Nguyen ◽  
Michele Geoffrion ◽  
Mary Lynn Cottee ◽  
...  
Keyword(s):  
Cell Death ◽  
Subcutaneous Administration ◽  
Peritoneal Macrophages ◽  
Necrotic Core ◽  
Endosomal Trafficking ◽  
Lipid Uptake ◽  
Core Formation ◽  
Aortic Sinus ◽  
Cholesterol Levels ◽  
Progression Of Atherosclerosis

ABSTRACTObjectivesDuring the advancement of atherosclerosis, the cellularity of the plaque is governed by the influx of monocyte-derived macrophages and their turnover via apoptotic and non-apoptotic forms of cell death. Previous reports have demonstrated that programmed necrosis, or necroptosis, of macrophages within the plaque contribute to necrotic core formation. Knockdown or inhibition of the necrosome components RIPK1 and RIPK3 slow the progression of atherosclerosis, and activation of the terminal step of necroptosis, MLKL, has been demonstrated in advanced human atherosclerotic plaques. However, whether MLKL directly contributes to lesion development and necrotic core formation has not been investigated.Approaches and ResultsMLKL expression was knocked down in atherogenic Apoe- knockout mice via subcutaneous administration of antisense oligonucleotides (ASO). During advanced atherogenesis, Mlkl knockdown potently reduced cell death in the plaque, with a significant reduction in the necrotic core. However, total lesion area in the aortic sinus remained unchanged. Furthermore, treatment with the MLKL ASO unexpectedly reduced circulating cholesterol levels compared to control ASO, while staining for lipids within the plaque was significantly increased. Peritoneal macrophages transfected with the MLKL ASO showed increased lipid loading upon incubation with modified cholesterol-rich lipoproteins. In lipid-loaded macrophages, MLKL co-localized with Rab7, a marker of the late endosome.ConclusionsThese studies confirm the requirement for MLKL as the executioner of necroptosis, and as such a significant contributor to the necrotic core during atherogenesis. We also identified a previously unknown role for MLKL in interacting with endosomal trafficking components to regulate lipid uptake in macrophages during atherogenesis.

Stress Concentrations of Vulnerable Plaques With a Composite Variable Core

2010 ◽  
Author(s):  
Eyass Massarwa ◽  
Aronis Ze’ev ◽  
Rami Eliasy ◽  
Rami Haj-Ali ◽  
Shmuel Einav
Keyword(s):  
Plaque Rupture ◽  
Necrotic Core ◽  
Intraplaque Hemorrhage ◽  
Plaque Morphology ◽  
Rapid Progression ◽  
Stress Concentrations ◽  
Coronary Syndrome ◽  
Fibrous Cap ◽  
Vulnerable Plaques ◽  
Life Threatening

Vulnerable plaques are inflamed, active, and growing lesions which are prone to complications such as rupture, luminal and mural thrombosis, intraplaque hemorrhage, and rapid progression to stenosis. It remains difficult to assess what factors influence the biomechanical stability of vulnerable plaques and promote some of them to rupture while others remain intact. The rupture of thin fibrous cap overlying the necrotic core of a vulnerable plaque is the principal cause of acute coronary syndrome. The mechanism or mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to a life threatening athero-thrombotic lesion are not fully understood. It has been widely assumed that plaque morphology is the major determinant of clinical outcome [1, 2]. Thin-cap fibroatheroma with a large necrotic core and a fibrous cap of < 65μm was describes as a more specific precursor of plaque rupture due to tissue stress.

Abstract T MP29: Contrast-Enhanced Ultrasound is Useful for Detection of Vulnerable Plaques

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Rie Motoyama ◽  
Kozue Saito ◽  
Shuichi Tonomura ◽  
Hatsue I Ueda ◽  
Hiroharu Kataoka ◽  
...  
Keyword(s):  
High Intensity ◽  
Necrotic Core ◽  
Intraplaque Hemorrhage ◽  
Contrast Enhanced Ultrasound ◽  
Histopathological Findings ◽  
Rapid Acquisition ◽  
Fibrous Cap ◽  
Vulnerable Plaques ◽  
Contrast Enhanced ◽  
Active Inflammation

Background and Purpose: Vulnerable plaques of carotid arteries are characterized as the presence of large necrotic core, intraplaque hemorrhage (IPH), intraplaque neovascularization (IPN), and active inflammation with thin fibrous cap. MRI is widely used for the qualitative evaluation of the plaques in vivo and the high-intensity plaques (HIP) on magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images indicate containing necrotic cores with IPH, which indicates vulnerable plaques. However, we encounter the symptomatic cases without the presence of HIP on MPRAGE in clinical practice. Recent studies showed the efficacy for the evaluation of IPN using contrast-enhanced ultrasound (CEUS). We aimed to assess the vulnerability of the plaques without high intensity on MPRAGE images using CEUS. Methods: Between July 2010 and June 2014, we enrolled 69 patients with internal carotid artery stenosis who underwent carotid endarterectomy (CEA) and preoperatively examined CEUS and MRI (MPRAGE). All plaques were evaluated with CEUS and the contrast effects were classified semi-quantitatively (grade 0: absent, 1: small, 2: large, 3: extensive). We also divided the plaques into two groups (HIP group or non-HIP group) based on the signal intensity of the plaques on MPRAGE images. The results of MRI and CEUS were compared with histopathological findings of CEA specimens. Results: Fifty-eight plaques of all 69 patients showed HIP (41 were symptomatic), and eleven plaques were non-HIP (five were symptomatic: amaurosis fugax in three, cerebral infarction in two). In non-HIP group, symptomatic plaques were more enhanced (three in grade 2, two in grade 3) than asymptomatic plaques (one in grade 0, five in grade 1) using CEUS. Histopathological findings of all five CEA specimens from symptomatic patients showed that extensive IPN, large necrotic core, and active inflammation with thin fibrous cap which indicated vulnerable plaques, but small amount of IPH. These histological findings were compatible with the results of CEUS and MRI findings. Conclusion: CEUS may be useful for diagnosis of vulnerable plaques without high intensity on MPRAGE images.

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