Plaque burden influences accurate classification of fibrous cap atheroma by in vivo optical coherence tomography in a porcine model of advanced coronary atherosclerosis

Poulsen, Christian Bo; Pedrigi, Ryan M.; Pareek, Nilesh; Kılıç, İsmail Doğu; Holm, Niels Ramsing; Bentzon, Jacob F.; Bøtker, Hans Erik; Falk, Erling; Krams, Rob; Silva, Ranil de

doi:10.4244/eij-d-17-01028

Cited by 4 publications

(2 citation statements)

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“…Namely, the Euarchontoglires clade that includes primates, rodents, and rabbits exhibit a strong pressure for gene preservation, whereas the Laurasiatheria clade is characterized by multiple independent events that led to the loss of PCSK9 in many species, such as pigs, bovine, camels, whales, bats, cats, dogs, bears, and horses ( 289 ). The loss of PCSK9 expression in pigs, suggests that studies of cholesterol metabolism therein would be advantageous for understanding cholesterol-related human diseases, as recently reported in D374Y-PCSK9 transgenics ( 152 ) resulting in hypercholesterolemic minipigs, a porcine model of advanced coronary atherosclerosis ( 290 ).…”

Section: Discussionmentioning

confidence: 92%

The Multifaceted Biology of PCSK9

2021

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This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating LDL-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain (CHRD), its binding to the secreted cytosolic cyclase associated protein 1 (CAP-1), and possibly another membrane-bound “protein X”. Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the anti-tumoral activity of CD8 + T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors (PCSK9i) that reduces by 50-60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 mAb or siRNA could be added to current immunotherapies in cancer/metastasis.

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Section: Discussionmentioning

confidence: 92%

The Multifaceted Biology of PCSK9

2021

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“…Plaque area was also found to positively correlate with K trans in plaques induced by low WSS, but this may be simply due to the larger space for NPs to accumulate (although no correlation was found in plaques induced by multidirectional WSS). Larger overall plaque size does not necessarily correspond to a more advanced phenotype [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Smooth muscle cells affect differential nanoparticle accumulation in disturbed blood flow-induced murine atherosclerosis

et al. 2021

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Atherosclerosis is a lipid-driven chronic inflammatory disease that leads to the formation of plaques in the inner lining of arteries. Plaques form over a range of phenotypes, the most severe of which is vulnerable to rupture and causes most of the clinically significant events. In this study, we evaluated the efficacy of nanoparticles (NPs) to differentiate between two plaque phenotypes based on accumulation kinetics in a mouse model of atherosclerosis. This model uses a perivascular cuff to induce two regions of disturbed wall shear stress (WSS) on the inner lining of the instrumented artery, low (upstream) and multidirectional (downstream), which, in turn, cause the development of an unstable and stable plaque phenotype, respectively. To evaluate the influence of each WSS condition, in addition to the final plaque phenotype, in determining NP uptake, mice were injected with NPs at intermediate and fully developed stages of plaque growth. The kinetics of artery wall uptake were assessed in vivo using dynamic contrast-enhanced magnetic resonance imaging. At the intermediate stage, there was no difference in NP uptake between the two WSS conditions, although both were different from the control arteries. At the fully-developed stage, however, NP uptake was reduced in plaques induced by low WSS, but not multidirectional WSS. Histological evaluation of plaques induced by low WSS revealed a significant inverse correlation between the presence of smooth muscle cells and NP accumulation, particularly at the plaque-lumen interface, which did not exist with other constituents (lipid and collagen) and was not present in plaques induced by multidirectional WSS. These findings demonstrate that NP accumulation can be used to differentiate between unstable and stable murine atherosclerosis, but accumulation kinetics are not directly influenced by the WSS condition. This tool could be used as a diagnostic to evaluate the efficacy of experimental therapeutics for atherosclerosis.

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