scholarly journals Melanocortin overexpression limits diet-induced inflammation and atherosclerosis in LDLR−/− mice

2018 ◽  
Vol 236 (3) ◽  
pp. 111-123 ◽  
Author(s):  
Salla Nuutinen ◽  
Liisa Ailanen ◽  
Eriika Savontaus ◽  
Petteri Rinne
Keyword(s):  
Atherosclerotic Plaque ◽  
Vascular Inflammation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plaque Formation ◽  
Western Diet ◽  
Low Density ◽  
Long Term Effects ◽  
Melanocortin System ◽  
Atherosclerotic Plaque Formation

Atherosclerosis is a chronic inflammatory disease of the arteries. The disease is initiated by endothelial dysfunction that allows the transport of leukocytes and low-density lipoprotein into the vessel wall forming atherosclerotic plaques. The melanocortin system is an endogenous peptide system that regulates, for example, energy homeostasis and cardiovascular function. Melanocortin treatment with endogenous or synthetic melanocortin peptides reduces body weight, protects the endothelium and alleviates vascular inflammation, but the long-term effects of melanocortin system activation on atheroprogression remain largely unknown. In this study, we evaluated the effects of transgenic melanocortin overexpression in a mouse model of atherosclerosis. Low-density lipoprotein receptor-deficient mice overexpressing alpha- and gamma3-MSH (MSH-OE) and their wild-type littermates were fed either a regular chow or Western-style diet for 16 weeks. During this time, their metabolic parameters were monitored. The aortae were collected for functional analysis, and the plaques in the aortic root and arch were characterised by histological and immunohistochemical stainings. The aortic expression of inflammatory mediators was determined by quantitative PCR. We found that transgenic MSH-OE improved glucose tolerance and limited atherosclerotic plaque formation particularly in Western diet-fed mice. In terms of aortic vasoreactivity, MSH-OE blunted alpha1-adrenoceptor-mediated vasoconstriction and enhanced relaxation response to acetylcholine, indicating improved endothelial function. In addition, MSH-OE markedly attenuated Western diet-induced upregulation of proinflammatory cytokines (Ccl2, Ccl5 and Il6) that contribute to the pathogenesis of atherosclerosis. These results show that the activation of the melanocortin system improves glucose homeostasis and limits diet-induced vascular inflammation and atherosclerotic plaque formation.

The lectin-like oxidized low-density-lipoprotein receptor: a pro-inflammatory factor in vascular disease

2007 ◽  
Vol 409 (2) ◽  
pp. 349-355 ◽  
Author(s):  
Sarah Dunn ◽  
Ravinder S. Vohra ◽  
Jane E. Murphy ◽  
Shervanthi Homer-Vanniasinkam ◽  
John H. Walker ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Atherosclerotic Plaque ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plaque Formation ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Oxidized Low Density Lipoprotein ◽  
Atherosclerotic Plaque Formation ◽  
Density Lipoprotein Receptor

Scavenger receptors are membrane glycoproteins that bind diverse ligands including lipid particles, phospholipids, apoptotic cells and pathogens. LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) is increasingly linked to atherosclerotic plaque formation. Transgenic mouse models for LOX-1 overexpression or gene knockout suggests that LOX-1 contributes to atherosclerotic plaque formation and progression. LOX-1 activation by oxidized LDL (low-density lipoprotein) binding stimulates intracellular signalling, gene expression and production of superoxide radicals. A key question is the role of leucocyte LOX-1 in pro-atherogenic lipid particle trafficking, accumulation and signalling leading to differentiation into foam cells, necrosis and plaque development. LOX-1 expression is elevated within vascular lesions and a serum soluble LOX-1 fragment appears diagnostic of patients with acute coronary syndromes. LOX-1 is increasingly viewed as a vascular disease biomarker and a potential therapeutic target in heart attack and stroke prevention.

scholarly journals The cellular biology of atherosclerosis with atherosclerotic lesion classification and biomarkers

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Leta Melaku ◽  
Addisu Dabi
Keyword(s):  
Atherosclerotic Plaque ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Plaque Formation ◽  
Necrotic Core ◽  
Atherosclerotic Plaques ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Lesion Classification

Abstract Background Atherosclerosis is a chronic lipid-driven inflammatory disease with infiltration of low-density lipoprotein and is considered as the pivotal step in plaque formation. The aim of the review is to get into the fine details of pathophysiologic mechanisms responsible for atherosclerosis with atherosclerotic lesion classification. It also provides a summary of current biomarkers other than the traditional risk factors so that new treatment modalities can emerge and reduce the morbidity and mortality associated with atherosclerosis. Main body In the classification of atherosclerosis made by American Heart Association (AHA), AHA Type I lesion is the earliest vascular change described microscopically. AHA Type II lesion is primarily composed of abundant macrophages. AHA Type III lesion is the earliest of progressive lesions, while AHA Type IV lesion consists of an acellular necrotic core. Various biomarkers are implicated in different stages of the pathophysiological mechanism of plaque formation and evolution. C Reactive Protein plays a direct role in promoting the inflammatory component of atherosclerosis. Fibrinogen was demonstrated to be elevated among patients with acute thrombosis. Higher leukocyte count is associated with a greater cardiovascular risk. Cytokines have been implicated in atheroma formation and complications. High rates of protease activated receptor expression are also induced by interleukin-6 secretion in atherosclerotic lesions and areas of vascular tissue injury. Cluster of differentiation 40 receptor and its ligand have been also detected in atherosclerotic plaques. Osteopontin, acidic phosphoprotein, and osteoprotegerin have emerged as novel markers of atherosclerotic plaque composition. There are also overproductions of matrix metalloproteinases in the rupture-prone regions and promote lipid-necrotic core formation in the atherosclerotic plaque. Myeloperoxidase has been proposed as a marker of plaque instability. Oxidized low-density lipoprotein receptor 1 provides a route of entry for oxidized low-density lipoprotein into the endothelium. A human atherosclerotic lesion also expresses lipoprotein-associated phospholipase A2. Short conclusion Atherosclerotic plaques are the battlefield between an unbalanced immune response and lipid accumulation in the intima of arteries. Most of the biomarkers associated with atherosclerosis are indicators of inflammatory response and will also be used for medical purposes.

scholarly journals Salidroside Decreases Atherosclerotic Plaque Formation in Low-Density Lipoprotein Receptor-Deficient Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Bu-Chun Zhang ◽  
Wei-Ming Li ◽  
Rong Guo ◽  
Ya-Wei Xu
Keyword(s):  
Atherosclerotic Plaque ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Plaque Formation ◽  
Lipid Lowering ◽  
Control Group ◽  
Active Components ◽  
Aortic Sinus ◽  
Atherosclerotic Plaque Formation

Salidroside is isolated fromRhodiola roseaand is one of the main active components inRhodiolaspecies. The present study was designed to evaluate the effects of Salidroside on atherosclerotic plaque formation in high-fat diet-(HFD-) fed female LDL receptor knockout (LDLr-/-) mice.LDLr-/-mice fed an atherogenic HFD for 12 weeks were divided into two groups. One group was administered Salidroside (50 mg/kg/oral gavage) daily for 8 weeks, while the control group was administered saline. Salidroside treatment reduced serum lipids levels and the plaque area through the arch to the abdominal aorta. Furthermore, Salidroside improved macrophage content and enhanced collagen and smooth muscle cells contents in the aortic sinus. These changes were associated with reduced MCP-1, VCAM-1, and VCAM-1 protein expression in atherosclerotic aortas. All these results suggest that Salidroside decreases atherosclerotic plaques formation via effects on lipid lowering and anti-inflammation in HFD-fed LDLr−/−mice.

Abstract 566: MicroRNA-146a Deficiency Prevents PCSK9 Gain-of-Function Mutation-induced Hypercholesterolemia in Mice

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Shayan Mohammadmoradi ◽  
Aida Javidan ◽  
Weihua Jiang ◽  
Jessica Moorleghen ◽  
Venkateswaran Subramanian
Keyword(s):  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Western Diet ◽  
Size Exclusion ◽  
Gel Chromatography ◽  
Low Density ◽  
Distribution Analysis ◽  
Gain Of Function ◽  
Ldl Particles

Background and Objective: Mimetic mediated activation of microRNA 146a (miR-146a) reduces atherosclerosis via suppression of nuclear factor-κB-driven inflammation in mice. The purpose of this study was to determine whether miR-146a influences plasma cholesterol in hypercholesterolemic mice. Methods and Results: To induce hypercholesterolemia, female C57BL/6 miR-146a WT (n=8) and miR-146a KO (n=8) mice were injected intraperitoneally with an adeno-associated viral vector (AAV) expressing the proprotein convertase subtilisin/kexin type 9 (PSCK9 D377Y) gain-of-function mutant at a dose of 3 x 10 10 genomic copies/mouse. After infection, mice were fed a Western diet (21% wt/wt milk fat; 0.15% wt/wt cholesterol) for sixteen weeks, and plasma PCSK9 and total cholesterol concentrations were monitored monthly using an enzymatic assay. Plasma PCSK9 concentrations were profoundly increased 4 weeks post injection (Baseline: WT - 179 ± 12 vs KO - 207 ± 12; Week 4: WT - 1700 ± 148 vs KO - 2689 ± 305 ng/ml) and remained significantly high during 16 weeks (WT - 882 ± 142 vs KO - 718 ± 109 ng/ml; p<0.05 vs baseline) of Western diet feeding. Consistent with increased plasma PCSK9 concentrations, plasma cholesterol concentrations were increased in both groups of mice. Interestingly, miR-146a KO group mice showed less significant increase in plasma cholesterol compared to WT group (Baseline: WT - 88 ± 3 vs KO - 83 ± 3; Week 4: WT - 328 ± 25 vs KO - 195 ± 18 mg/dl) irrespective of the comparable plasma PCSK9 concentrations. Also, lipoprotein distribution analysis with size exclusion gel chromatography revealed that miR-146a KO mice showed a strong reduction in high density lipoprotein (HDL) particles while very low density lipoprotein (VLDL) and low density lipoprotein (LDL) particles were not affected. Conclusion: Our findings suggests that miR146a plays a critical role in the regulation of HDL particles in PCSK9 gain-of-function mutant-induced hypercholesterolemia in mice. Future studies will identify gene targets influenced by miR-146a in regulating HDL-cholesterol in hypercholesterolemic mice.

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