Spontaneous experimental atherosclerosis in hypercholesterolemic mice advances with ageing and correlates with mitochondrial reactive oxygen species. | LitMetric
Dept of Structural and Functional Biology, Biology Institute, Campinas, SP, Brazil. Electronic address:
Published: August 2018
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Article Abstract
Ageing and atherosclerosis are associated with oxidative stress. Mitochondrial redox function declines with ageing. Here we tested whether ageing LDL receptor knockout mice (LDLr) develop spontaneous atherosclerosis and whether mitochondrial reactive oxygen species (mtROS) correlate with atherosclerosis. Compared with young mice, aged LDLr mice exhibited 20-fold larger aortic lesion size, although the plasma cholesterol levels did not vary between age groups. The lesion sizes increased exponentially from 3 to 24months of age (r=0.92, p=0.0001) and were correlated with mtROS across the age range (r=0.81, p=0.0001). Thus, LDLr mice develop spontaneous diet-independent atherosclerosis, that advances exponentially with ageing. We propose that age related increases in mtROS contribute to accelerate atherosclerosis development in hypercholesterolemic mice.
Protein Kinase C - epsilon (PKCɛ) is involved in diverse cellular processes such as migration, growth, differentiation, and survival. Public geneset analysis of human atherosclerotic plaque tissue revealed that PKCɛ expression is inversely correlated with plaque size and vulnerability. Similarly, peritoneal macrophages (MØ) from hypercholesterolemic mice have significantly lower PKCɛ expression.
Epigenetic modifications play an important role in disturbed flow (d-flow) induced atherosclerotic plaque formation. By analysing a scRNA-seq dataset of the left carotid artery (LCA) under d-flow conditions, we found that Jarid1b (KDM5B) was upregulated primarily in a subcluster of endothelial cells in response to d-flow stimulation. We therefore investigated the mechanism of KDM5B expression and the role of KDM5B in endothelial cell.
The asialoglycoprotein receptor 1 (ASGR1), a multivalent carbohydrate-binding receptor that primarily is responsible for recognizing and eliminating circulating glycoproteins with exposed galactose (Gal) or N-acetylgalactosamine (GalNAc) as terminal glycan residues, has been implicated in modulating the lipid metabolism and reducing cardiovascular disease burden. In this study, we investigated the impact of ASGR1 deficiency (ASGR1 on atherosclerosis by evaluating its effects on plaque formation, lipid metabolism, circulating immunoinflammatory response, and circulating N-glycome under the hypercholesterolemic condition in ApoE-deficient mice. After 16 weeks of a western-type diet, ApoE/ASGR1 mice presented lower plasma cholesterol and triglyceride levels compared to ApoE.
Vascular Biology Center, Augusta University, Medical College of Georgia, Augusta, GA, 30912, USA; Department of Pharmacology and Toxicology, Augusta University, Medical College of Georgia, Augusta, GA, 30912, USA. Electronic address:
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. Clinical and experimental data demonstrated that circulating monocytes internalize plasma lipoproteins and become lipid-laden foamy cells in hypercholesterolemic subjects. This study was designed to identify the endocytic mechanisms responsible for foamy monocyte formation, perform functional and transcriptomic analysis of foamy and non-foamy monocytes relevant to ASCVD, and characterize specific monocyte subsets isolated from the circulation of normocholesterolemic controls and hypercholesterolemic patients.
Background: Accumulating evidence indicates that coronary microvascular dysfunction (CMD) caused by hypercholesterolemia can lead to myocardial ischemia, with or without obstructive atherosclerotic coronary artery disease. However, the molecular pathways associated with compromised coronary microvascular function before the development of myocardial ischemic injury remain poorly defined. In this study, we investigated the effects of hypercholesterolemia on the function and integrity of the coronary microcirculation in mice and the underlying mechanisms.
