Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events‐a novel insight into plaque rupture by scanning electron microscopy

Abela, Mark; Aziz, Kusai

doi:10.1002/sca.4950280101

Cited by 110 publications

(85 citation statements)

References 30 publications

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“…In contrast, previous studies concluded that CholM crystals were present in ruptured human (41) and rabbit plaques (42) by the indirect observation of "cholesterol clefts." Abela and Aziz (43) showed that during cholesterol crystallization, the expansion of sharpedged crystals could damage the fibrous cap.…”

Section: Discussionmentioning

confidence: 99%

A robust rabbit model of human atherosclerosis and atherothrombosis

Phinikaridou

Hallock

Qiao

et al. 2009

Journal of Lipid Research

111

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Disruption and thrombosis of atherosclerotic plaques cause most acute cardiovascular events, but their systematic study has been hampered by the lack of suitable animal models. To assess the value of a modified rabbit model of atherothrombosis, we performed detailed histology of rabbit aortic plaques. Atherosclerosis was induced with a high cholesterol diet fed 2 weeks prior to and 6 weeks after balloon injury of the aorta, followed by 4 weeks of normal diet. We found six out of eight types of plaques cataloged by the American Heart Association in the rabbit aorta. Vulnerable plaques were defined as those with attached platelet and fibrin-rich thrombi after pharmacological triggering with Russellʼs viper venom and histamine. Ruptured plaques had, as also described for human plaques: i) marked medial and adventitial changes, including neovascularization and inflammation; ii) cholesterol monohydrate crystals and liquid crystalline cholesterol esters in the intima and the fibrous cap; and iii) inflamed, thin fibrous caps. Increased cholesterol monohydrate area, internal elastic lamina area, positive remodeling, fibrous cap inflammation, adventitia breakdown, and inflammation were independent predictors of plaque disruption. Our findings reveal novel insights into plaque vulnerability and could guide the design of noninvasive imaging approaches for detecting and treating high-risk plaques.-Phinikaridou, A., K. J. Hallock, Y. Qiao, and J. A. Hamilton. A robust rabbit model of human atherosclerosis and atherothrombosis. J. Lipid Res. 2009. 50: 787-797.

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Section: Discussionmentioning

confidence: 99%

A robust rabbit model of human atherosclerosis and atherothrombosis

Phinikaridou

Hallock

Qiao

et al. 2009

Journal of Lipid Research

111

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“…IP 3 binds to and opens the IP 3 receptor embedded in the endoplasmic reticulum (ER) membrane, releasing into the cytoplasm calcium stored in the ER. Free calcium can bind calmodulin (CaM) and many other effectors.…”

Section: Other Adapters and Enzymes Link Insr To Multiple Pathwaysmentioning

confidence: 99%

“…Novel PKC enzymes (PKC␦, -, -, and -) are activated by DAG but not calcium. Atypical PKCs, including PKC, -, and -, can be activated by PIP 3 or ceramide. All the PKC enzymes are further activated by PDK1 in PIP 3 -enriched cell membranes.…”

Section: Other Adapters and Enzymes Link Insr To Multiple Pathwaysmentioning

confidence: 99%

“…Grb2 brings with it (bound to SH3 domains) the RasGEF Sos, which then activates Ras. Sos activity is partially dependent on PIP 3 . Active Sos mediates exchange of GDP for GTP on Ras.…”

Section: Multiple G Proteins Are Activated By Insulin Signalingmentioning

confidence: 99%

“…These ROS reversibly inhibit assorted protein tyrosine phosphatases (PTP) as well as the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten). PTEN acts to cleave the 3 phosphate on PIP 3 . PTEN and the various tyrosine phosphatases can be so active that, without inactivation, no signal can be propagated.…”

Section: Signaling Cassettes Activated By Rtk Are Mutually Supportivementioning

confidence: 99%

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Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

390

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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