Characteristics of Intact and Ruptured Atherosclerotic Plaques in Brachiocephalic Arteries of Apolipoprotein E Knockout Mice

Abstract

Abstract-The brachiocephalic arteries of fat-fed apolipoprotein E knockout mice develop plaques that frequently rupture and form luminal thromboses. The morphological characteristics of plaques without evidence of instability or with healed previous ruptures (intact) and vessels with acutely ruptured plaques (ruptured) have now been defined, to understand the process of plaque destabilization in more detail. Ninety-eight apolipoprotein E knockout mice were fed a diet supplemented with 21% lard and 0.15% cholesterol, for 5 to 59 weeks. Of these 98 mice, 51 had an acutely ruptured plaque in the brachiocephalic artery. See cover and page 713The apolipoprotein E (apoE) knockout mouse has become established as a model of hypercholesterolemia and atherosclerotic lesion development. 2-5 After 6 months on a high-fat diet, advanced fibrous plaques are observed with thin luminal elastin and collagen fibers capping small lipid-rich globular lesions. 5 Four studies have now reported that the lesions of apoE knockout mice can spontaneously become unstable. 6 -9 The brachiocephalic (also known as the innominate) artery, which is the first branch from the aortic arch, bifurcating to form the right common carotid artery and the right subclavian artery, is a site of predilection for the development of such vulnerable lesions. It provides a small and well-defined area in which to study the progressive loss of plaque stability and, eventually, rupture.In a previous study, 7 a small number of apoE knockout mice were examined. All of these had died suddenly, which meant that it was not possible to perfusion fix their arteries. In the current study, the development and morphology of brachiocephalic artery plaques have been characterized in a cohort of 98 apoE knockout mice. Ruptured and intact lesions have been compared both in animals dying suddenly and in those that were perfusion fixed after scheduled termination. Methods AnimalsHomozygous apoE knockout mice 10 were obtained from Charles River Laboratories (Manston, Kent, UK). The strain background of these animals was 50% C57BL/6, 50% 129SvJ, as determined by fingerprinting of tail-tip DNA. The housing and care of the animals and all the procedures used in these studies were performed in accordance with the guidelines and regulations of the University of Bristol and the United Kingdom Home Office. HusbandryStarting at 6 to 8 weeks of age, 98 apoE knockout mice (51 male) were fed a high-fat rodent diet containing 21% fat from lard and supplemented with 0.15% (wt/wt) cholesterol (Special Diets Services) for a period of 5 to 59 weeks. Cages were checked daily, and any animals that had suffered sudden death were immediately removed and processed for histological examination. TerminationAnimals were anesthetized by intraperitoneal injection of sodium pentobarbitone before exsanguination by arterial perfusion via the

Temporal shifts in clinical presentation and underlying mechanisms of atherosclerotic disease

“…The generation of genetically modified mice on an atherosclerotic background exponentially increased the published papers on genes that may influence plaque growth and lesion characteristics 97 98 . The interpretations of many interventions in mice often refer back to the early pathological descriptions of the "vulnerable plaque" deemed responsible for triggering most thrombotic occlusive events in humans 99 . Despite its undeniable utility for probing specific molecular mechanisms, atherosclerosis-prone mice differ in a multitude of important respects from humans with arterial disease 100 101 .…”

Serum Amyloid A, but Not C-Reactive Protein, Stimulates Vascular Proteoglycan Synthesis in a Pro-Atherogenic Manner

“…Atherosclerosis was quantified in the aortic root, en face aorta, and brachiocephalic artery as previously described. 14,39,40 Immunohistochemical staining was performed on adjacent aortic root sections as previously described. 33 …”

Rupture of the Brachiocephalic Trunk in A 10 Month Old Boston Terrier Bitch at Alberton Veterinary Clinic Johannesburg: A Post-Mortem Case Report

“…It is also clear from the history that this dog was fed on a commercial veterinary diet that is low in fats, which was unlikely to cause the de-velopment of plaques (implicated in degenerative vascular changes) and subsequent brachiocephalic rupture as reported in experimentally fed to genetically engineered Apolipoprotein E knockout mice by Williams, Johnson [7]. The diagnosis of brachiocephalic rupture in the current case was not made during ante mortem diagnostic work-up but only reached after post mortem examination, which is in accord with the report of Arimura, Machida [1].…”

“…In recent years, however, it has become possible to manipulate feeding of genetically engineered Apolipoprotein E to knockout mice and cause the development of arterial plaques which rupture within 46 ± 3 weeks [7]. Even in these cases where plaques have been purposely induced, spontaneous rupture has not been captured at the time of occurrence.…”