Atherogenesis during low level hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque.

Abstract

This study focuses on the formation of lesions of atherosclerosis in the aortas and iliac arteries of nonhuman primates (Macaca nemestrtna) maintained on a low level hypercholesterolemlc diet (plasma cholesterol 200 to 400 mg/dl) for 2, 3, or 3.5 years. Advanced lesions, or fibrous plaques, were found In all of the animals. The extent and severity of the lesions were closely related to the level and duration of hypercholesterolemla. The presence of monocyte-macrophages, T-tymphocytes, and smooth muscle cells, and the interactions of those cells that precede fibrous plaque formation In these long-term, relatively low level hypercholesterolemlc monkeys were similar to those observed In previously published studies of high level hypercholesterolemia In nonhuman primates, with one principal difference: the fibrous plaques In the longer-term, low level hypercholesterolemlc animals contained Increased amounts of fibrous connective tissue, more smooth muscle cells, and fewer macrophages. As In the studies with high levels of hypercholesterolemla, fibrous plaques were more frequently observed In the abdominal aorta and lilac arteries than In the thoracic aorta and aortic arch. Fibrous plaques were preferentially located at the branches and bifurcations of the arteries. These anatomic sites were consistent with those that contained fatty streaks and flbrofatty lesions In the animals fed the diet for shorter periods of time. These data are compatible with the proposal that many of the fatty streaks are converted to flbrofatty lesions, some of which ultimately become converted to fibrous plaques. (Arteriosclerosis 10:178-187, March/April 1990) I n the first article in this series, 1 we described the cellular interactions that precede and are responsible for the formation of the fatty streak in nonhuman primates maintained on low level hypercholesteroiemic diets. Deposition of lipld in the artery wall, adhesion of circulating leukocytes to endothelium, and subsequent entry of the leukocytes into the artery wall are the initial events observed during cholesterol feeding. In our studies, many of the monocytes that enter and localize within the arterial intima became lipld-tllled macrophages and formed the earliest fatty streaks. Small numbers of T-rymphocytes, principally CD8-posrtive cells with a few CD4-positive cells, were components of all of the fatty streaks. As the lesions progressed, the surfaces of the fatty streaks became increasingly irregular, and endothelial detachment and remodeling occurred, often resulting in exposure of the foam cells to the lumen. Platelet microthrombi were frequently observed attached to the surfaces of the exposed macrophages. In this part of the report, we present the observations made during low level hypercholesterolemia in monkeys (Macaca nemestrina) maintained in this state for 2 to 3.5 years. We will focus on the cellular interactions and the changes that occurred during the progression of the fatty streaks to form fibrous plaques. The chronologic changes in the cellular components o...

Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion.

“…In addition, it should be mentioned that the greater part of the endothelial barrier has been destroyed or at least altered (vascular injury type II or III with endothelial denudation) (40,41) in the advanced atherosclerotic regions that we used in our investigations. Therefore, to examine NF-B activation in endothelial cells, cryostat sections were made from tissue with less advanced atherosclerosis, hence still displaying a rather intact endothelial layer.…”

Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. I. Is the extent of atherosclerosis related to resistance of LDL to oxidation?

“…For the animals whose tissues were used for quantitation of lesion area, the thoracic and abdominal aortas and iliac arteries were rapidly removed after ketamine anesthesia and a lethal injection of phenobarbital. The vessels were cut open longitudinally, washed well with sterile PBS, and cut into 16 segments: six for the thoracic aorta, six for the abdominal aorta, and two each for the left and right iliac arteries, as previously described (23, 25,26). Identical segments were taken from each animal using the distance from branch points as an internal reference.…”

“…Advanced fibrous plaques were first observed at similar anatomic sites in animals maintained at the same plasma cholesterol levels for 5-13 mos. The level and duration of hypercholesterolemia of these monkeys have consistently correlated with the stage of lesion development at specific anatomic sites (24)(25)(26).…”

Differential accumulation of intimal monocyte-macrophages relative to lipoproteins and lipofuscin corresponds to hemodynamic forces on cardiac valves in mice.

“…), were fed an atherogenic diet based on the Thomas-Hartroft formula, together with standard mouse chow (Purina #5005) in a 1:3 ratio for [15][16][17][18][19][20][21][22] weeks. This diet contained 9% fat, 1.25% cholesterol, and 0.5% cholic acid.…”