scholarly journals scFv-Anti-LDL(-)-Metal-Complex Multi-Wall Functionalized-Nanocapsules as a Promising Tool for the Prevention of Atherosclerosis Progression

2021 ◽  
Vol 8 ◽  
Author(s):  
Marcela Frota Cavalcante ◽  
Márcia Duarte Adorne ◽  
Walter Miguel Turato ◽  
Marina Kemmerer ◽  
Mayara Klimuk Uchiyama ◽  
...  
Keyword(s):  
Single Chain ◽  
Chain Fragment ◽  
Atherosclerosis Progression ◽  
Protein Levels ◽  
Promising Tool ◽  
Atherosclerotic Lesions ◽  
Single Chain Fragment Variable ◽  
Ldl Uptake ◽  
Prevention Of Atherosclerosis

Atherosclerosis can be originated from the accumulation of modified cholesterol-rich lipoproteins in the arterial wall. The electronegative LDL, LDL(-), plays an important role in the pathogenesis of atherosclerosis once this cholesterol-rich lipoprotein can be internalized by macrophages, contributing to the formation of foam cells, and provoking an immune-inflammatory response. Herein, we engineered a nanoformulation containing highly pure surface-functionalized nanocapsules using a single-chain fragment variable (scFv) reactive to LDL(-) as a ligand and assessed whether it can affect the LDL(-) uptake by primary macrophages and the progression of atherosclerotic lesions in Ldlr−/− mice. The engineered and optimized scFv-anti-LDL(-)-MCMN-Zn nanoformulation is internalized by human and murine macrophages in vitro by different endocytosis mechanisms. Moreover, macrophages exhibited lower LDL(-) uptake and reduced mRNA and protein levels of IL1B and MCP1 induced by LDL(-) when treated with this new nanoformulation. In a mouse model of atherosclerosis employing Ldlr−/− mice, intravenous administration of scFv-anti-LDL(-)-MCMN-Zn nanoformulation inhibited atherosclerosis progression without affecting vascular permeability or inducing leukocytes-endothelium interactions. Together, these findings suggest that a scFv-anti-LDL(-)-MCMN-Zn nanoformulation holds promise to be used in future preventive and therapeutic strategies for atherosclerosis.

scholarly journals Immunotoxins Containing Recombinant Anti-CTLA-4 Single-Chain Fragment Variable Antibodies and Saporin: In Vitro Results and In Vivo Effects in an Acute Rejection Model

2001 ◽  
Vol 167 (8) ◽  
pp. 4222-4229 ◽  
Author(s):  
Pier-Luigi Tazzari ◽  
Letizia Polito ◽  
Andrea Bolognesi ◽  
Maria-Pia Pistillo ◽  
Paolo Capanni ◽  
...  
Keyword(s):  
Acute Rejection ◽  
Single Chain ◽  
Chain Fragment ◽  
Single Chain Fragment Variable ◽  
In Vivo Effects ◽  
Single Chain Fragment

Abstract 136: Identification of Melanoregulin as Novel Marker for Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Silvia Aldi ◽  
Ljubica Perisic ◽  
Mariette Lengquist ◽  
Malin Kronqvist ◽  
Joy Roy ◽  
...  
Keyword(s):  
Carotid Plaque ◽  
Vascular Diseases ◽  
Human Monocyte ◽  
Foam Cells ◽  
Aortic Tissue ◽  
Atherosclerosis Progression ◽  
Protein Levels ◽  
Atherosclerotic Lesions ◽  
Novel Biomarkers ◽  
Human Carotid

Introduction: Novel biomarkers identification in atherosclerosis is needed for early detection/intervention of vascular diseases. Impaired lysosomal function and autophagy cause abnormal lipid accumulation in foam cells and contribute to atherosclerosis progression. By microarray of human carotid plaques in the Biobank of Karolinska Endarterectomies (BiKE), we found that melanoregulin (MREG), a protein associated with lysosomes, phagocytosis and autophagy and previously not associated with atherosclerosis, was significantly up-regulated in symptomatic (S) versus asymptomatic (AS) patients. MREG expression was also significantly correlated to inflammatory, lipid and endo/lysosome markers. Hypothesis: We hypothesized that MREG modulates clearance of engulfed lipids and extracellular material in lipid-loaded foam cells. Methods: MREG mRNA and protein levels were evaluated in human carotid plaque tissue from S and AS patients by qPCR and immunohistochemistry, respectively. MREG, together with lysosome and lipid markers (LAMP2 and PLIN2 respectively) was identified by immunofluorescence in human monocyte cells (THP-1), loaded with modified LDL. To investigate autophagy/MREG correlation, THP-1 cells were incubated with autophagy inhibitor (chloroquine, CQ) and MREG mRNA was assessed by qPCR. Results: MREG mRNA is elevated in human atherosclerotic lesions versus normal artery (11.21 folds, P<0.0001). In human aortic tissue MREG expression is correlated to the lesion progression and localizes in infiltrating macrophage-derived foam cells. In the human carotid plaque, MREG co-localizes with CD68+ and PLIN2+ cells, lined to the necrotic core. MREG protein was also detected in PMA-differentiated THP-1 cells. In lipid-loaded THP-1, MREG is co-localized with lysosomal LAMP2. Moreover, MREG expression is increased in THP-1 cells by incubation with PMA, starving medium and CQ. Conclusions: We show here for the first time that MREG is expressed in atherosclerotic lesions and is associated with endo/lysosomes in human macrophages. Furthermore we show that autophagy inhibition increases MREG mRNA expression. Future studies will investigate how MREG expression levels will affect phagocytic activity of lipid-loaded macrophages.

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