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.

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 Cholesterol Acceptors Regulate the Lipidome of Macrophage Foam Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3784 ◽  
Author(s):  
Antoni Paul ◽  
Todd A. Lydic ◽  
Ryan Hogan ◽  
Young-Hwa Goo
Keyword(s):  
High Density Lipoprotein ◽  
Free Cholesterol ◽  
Foam Cell ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Apolipoprotein A ◽  
Lipid Species ◽  
Macrophage Foam Cells

Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent lipidomics of human atherosclerotic plaques also identified that oxidized sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis progresses. While it is known that these lipids regulate expression of pro-inflammatory genes linked to plaque instability, how cholesterol acceptors impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, remains unexplored. Using lipidomics analyses, we found cholesterol acceptors remodel foam cell lipidomes. Lipid subclass analyses revealed various oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human plaques were significantly reduced by cholesterol acceptors, especially by apoA-I. These results indicate that the function of lipid-poor apoA-I is not limited to the efflux of cholesterol and phospholipids but suggest that apoA-I serves as a major regulator of the foam cell lipidome and might play an important role in reducing multiple lipid species involved in the pathogenesis of atherosclerosis.

Development of Nanoparticle Probes for In Vivo Imaging of Atherosclerotic Plaques

2012 ◽  
Author(s):  
Zihao Zhang ◽  
Sheng Tong ◽  
Gang Bao
Keyword(s):  
Surface Defects ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Necrotic Core ◽  
Intraplaque Hemorrhage ◽  
Atherosclerotic Plaques ◽  
Nanoparticle Probes ◽  
Arterial Lumen ◽  
Inflammatory Macrophage

Atherosclerosis, the formation of fatty plaques in the arterial lumen, is mediated by inflammatory macrophage infiltration in the lesion and ingestion of low-density lipoprotein (LDL), forming foam cells. Its progression will likely form a large necrotic core and fibrotic cap surface defects. The resulting intraplaque hemorrhage causes red blood cell infiltration and hemoglobin abundance, which oxidizes LDL to form cholesterol crystal aggregates (1). Hemorrhagic plaques could rupture and form artery-blocking emboli. Thus, it is critical to develop a tool to detect and locate unstable hemorrhagic plaques in live specimens.

scholarly journals Lung exposure to lipopolysaccharide causes atherosclerotic plaque destabilisation

2016 ◽  
Vol 48 (1) ◽  
pp. 205-215 ◽  
Author(s):  
Jen Erh Jaw ◽  
Masashi Tsuruta ◽  
Yeni Oh ◽  
John Schipilow ◽  
Yuki Hirano ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Inflammation ◽  
Cardiovascular Events ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Saline Control ◽  
Atheromatous Plaque ◽  
Vascular Events ◽  
Plaque Instability ◽  
Brachiocephalic Trunk

Epidemiological studies have implicated lung inflammation as a risk factor for acute cardiovascular events, but the underlying mechanisms linking lung injury with cardiovascular events are largely unknown.Our objective was to develop a novel murine model of acute atheromatous plaque rupture related to lung inflammation and to investigate the role of neutrophils in this process.Lipopolysaccharide (LPS; 3 mg·kg−1) or saline (control) was instilled directly into the lungs of male apolipoprotein E-null C57BL/6J mice following 8 weeks of a Western-type diet. 24 h later, atheromas in the right brachiocephalic trunk were assessed for stability ex vivo using high-resolution optical projection tomography and histology. 68% of LPS-exposed mice developed vulnerable plaques, characterised by intraplaque haemorrhage and thrombus, versus 12% of saline-exposed mice (p=0.0004). Plaque instability was detectable as early as 8 h post-intratracheal LPS instillation, but not with intraperitoneal instillation. Depletion of circulating neutrophils attenuated plaque rupture.We have established a novel plaque rupture model related to lung injury induced by intratracheal exposure to LPS. In this model, neutrophils play an important role in both lung inflammation and plaque rupture. This model could be useful for screening therapeutic targets to prevent acute vascular events related to lung inflammation.

scholarly journals Potential Mechanisms and Effects of Efferocytosis in Atherosclerosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Lili Wang ◽  
Hongxia Li ◽  
Yuhan Tang ◽  
Ping Yao
Keyword(s):  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Plaque Rupture ◽  
Cerebrovascular Diseases ◽  
Necrotic Core ◽  
Dynamic Regulation ◽  
Physiological Conditions ◽  
Great Progress ◽  
Abnormal Accumulation

Atherosclerosis (AS) is the main pathological basis for the development of cardio-cerebrovascular diseases. Abnormal accumulation of apoptotic and necrotic cells resulted in plaque enlargement, necrotic core formation and plaque rupture in AS. Under physiological conditions, apoptotic cells (ACs) could be effectively phagocytized and cleared by phagocyte-mediated efferocytosis. In contrast, the clearance efficiency of ACs in AS plaque was much lower because of the impaired efferocytosis in AS. Recent findings have made great progress on the molecular mechanisms of efferocytosis process and dynamic regulation, and its dysfunction on organismal health. Yet, there are still few effective treatments for this process. This article reviews the mechanism of efferocytosis and the role of efferocytosis in AS, highlighting a novel therapeutic strategy for AS, which mainly prevents the progression of plaque by targeting efferocytosis.

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.

scholarly journals Relationship Between Autophagy and Metabolic Syndrome Characteristics in the Pathogenesis of Atherosclerosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Jing Xu ◽  
Munehiro Kitada ◽  
Yoshio Ogura ◽  
Daisuke Koya
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Plaque Rupture ◽  
Cell Formation ◽  
Degradation Process ◽  
Vascular Wall ◽  
Foam Cell Formation ◽  
Plaque Instability

Atherosclerosis is the main cause of mortality in metabolic-related diseases, including cardiovascular disease and type 2 diabetes (T2DM). Atherosclerosis is characterized by lipid accumulation and increased inflammatory cytokines in the vascular wall, endothelial cell and vascular smooth muscle cell dysfunction and foam cell formation initiated by monocytes/macrophages. The characteristics of metabolic syndrome (MetS), including obesity, glucose intolerance, dyslipidemia and hypertension, may activate multiple mechanisms, such as insulin resistance, oxidative stress and inflammatory pathways, thereby contributing to increased risks of developing atherosclerosis and T2DM. Autophagy is a lysosomal degradation process that plays an important role in maintaining cellular metabolic homeostasis. Increasing evidence indicates that impaired autophagy induced by MetS is related to oxidative stress, inflammation, and foam cell formation, further promoting atherosclerosis. Basal and mild adaptive autophagy protect against the progression of atherosclerotic plaques, while excessive autophagy activation leads to cell death, plaque instability or even plaque rupture. Therefore, autophagic homeostasis is essential for the development and outcome of atherosclerosis. Here, we discuss the potential role of autophagy and metabolic syndrome in the pathophysiologic mechanisms of atherosclerosis and potential therapeutic drugs that target these molecular mechanisms.

MCL-1 Critically Regulates Survival Of T-Lymphocyte Non-Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4246-4246
Author(s):  
Sabine Spinner ◽  
Kelly Gemma ◽  
Marco Herold ◽  
Konstanze Pechloff ◽  
Giuliano Crispatzu ◽  
...  
Keyword(s):  
Cell Death ◽  
Hodgkin Lymphoma ◽  
T Lymphocyte ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Whole Body ◽  
Resistance To Therapy ◽  
Non Hodgkin Lymphoma ◽  
Allelic Deletion

Abstract The heterogeneous subgroup of T-lymphocyte non-Hodgkin lymphoma (T-NHL) exhibits an aggressive growth pattern and is relatively insensitive to chemotherapy. The molecular mechanisms of survival and resistance to therapy remain largely undefined. We hypothesized that BCL-2 proteins with anti-apoptotic properties protect T-NHL cells from cell death, cause resistance to therapy and therefore represent an attractive target for therapy. MCL-1 potently protects physiologically healthy T-lymphocytes from cell death, but its function in transformed T-cells is incompletely understood. We therefore dissected the role of MCL-1 using in silico meta-analyses on available gene expression data on human primary T-NHL samples. We identified MCL-1 as the primary BCL-2 family protein to be highly expressed across most major T-NHL subsets. Expression of MCL-1 was restricted to its anti-apoptotic full-length splice variant as opposed to its pro-apoptotic short isoform. To functionally characterize the requirement for MCL-1, we utilized a T-NHL mouse model, which is based on four consecutive low-dose whole-body γ-irradiations in 4 week-old mice resulting in the development of T-NHL mimicking human peripheral T-cell lymphoma. We utilized mice harbouring loxP-flanked Mcl-1 or loxP-flanked Bcl-x(L) in combination with inducible Cre recombinase to conditionally delete the gene of interest after lymphoma induction. Interestingly, conditional deletion of only one allele of Mcl-1 in fully established primary T-NHL cells ex vivo led to a significant and specific loss of viability, whereas survival remained unaffected by full deletion of Bcl-x(L). Reduced MCL-1 levels resulted in substantially elevated sensitivity to standard chemotherapeutics such as anthracyclins, cyclophosphamide and etoposide. In addition, mono-allelic deletion of Mcl-1 in vivo prolonged survival of lymphoma-bearing mice. Together, these data argue that anti-apoptotic MCL-1 is the single most important BCL-2 family member involved in the sustained survival of T-NHL. Disclosures: Strasser: Genentech Inc: Consultancy.

scholarly journals NecroX-7 reduces necrotic core formation in atherosclerotic plaques of Apoe knockout mice

2016 ◽  
Vol 252 ◽  
pp. 166-174 ◽  
Author(s):  
Mandy O.J. Grootaert ◽  
Dorien M. Schrijvers ◽  
Hanne Van Spaendonk ◽  
Annelies Breynaert ◽  
Nina Hermans ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Necrotic Core ◽  
Atherosclerotic Plaques ◽  
Core Formation ◽  
Apoe Knockout Mice

scholarly journals Positron Emission Tomography Imaging of Macrophages in Atherosclerosis with 18F-GE-180, a Radiotracer for Translocator Protein (TSPO)

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Sanna Hellberg ◽  
Heidi Liljenbäck ◽  
Olli Eskola ◽  
Veronique Morisson-Iveson ◽  
Matthew Morrison ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Positron Emission Tomography Imaging ◽  
Translocator Protein ◽  
Atherosclerotic Plaques ◽  
Third Generation ◽  
Tissue Samples ◽  
Contrast Enhanced Ct

Intraplaque inflammation plays an important role in the progression of atherosclerosis. The 18 kDa translocator protein (TSPO) expression is upregulated in activated macrophages, representing a potential target to identify inflamed atherosclerotic plaques. We preclinically evaluated 18F-GE-180, a novel third-generation TSPO radioligand, in a mouse model of atherosclerosis. Methods. Nine hypercholesterolemic mice deficient in low density lipoprotein receptor and apolipoprotein B48 (LDLR−/−ApoB100/100) and six healthy C57BL/6N mice were injected with 10 MBq of 18F-GE-180. Specificity of binding was demonstrated in three LDLR−/−ApoB100/100 mice by injection of nonradioactive reference compound of 18F-GE-180 before 18F-GE-180. Dynamic 30-minute PET was performed followed by contrast-enhanced CT, and the mice were sacrificed at 60 minutes after injection. Tissue samples were obtained for ex vivo biodistribution measurements, and aortas were cut into serial cryosections for digital autoradiography. The presence of macrophages and TSPO was studied by immunohistochemistry. The 18F-GE-180 retention in plaque areas with different macrophage densities and lesion-free vessel wall were compared. Results. The LDLR−/−ApoB100/100 mice showed large, inflamed plaques in the aorta. Autoradiography revealed significantly higher 18F-GE-180 retention in macrophage-rich plaque areas than in noninflamed areas (count densities 150 ± 45 PSL/mm2 versus 51 ± 12 PSL/mm2, p<0.001). Prominent retention in the vessel wall without plaque was also observed (220 ± 41 PSL/mm2). Blocking with nonradioactive GE-180 diminished the difference in count densities between macrophage-rich and noninflamed areas in atherosclerotic plaques and lowered the count density in vessel wall without plaque. Conclusion. 18F-GE-180 shows specific uptake in macrophage-rich areas of atherosclerotic plaques in mice. However, retention in atherosclerotic lesions does not exceed that in lesion-free vessel wall. The third-generation TSPO radioligand 18F-GE-180 did not show improved characteristics for imaging atherosclerotic plaque inflammation compared to previously studied TSPO-targeting tracers.

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