Influence of serum cholesterol on atherogenesis and intimal hyperplasia after angioplasty: inhibition by amlodipine

Abstract

The objectives of the present study were to determine whether serum hypercholesterolemia (HC) promotes the development of spontaneous and angioplasty-induced lesions and whether amlodipine inhibits these lesions and cellular processes underlying their genesis. Rabbits were fed normal, 0.5%, or 2% cholesterol diets for 9 wk, which resulted in the development of increasing HC. After week one, balloon dilation of the abdominal aorta was performed while the thoracic aorta was not disturbed and monitored for the development of spontaneous lesions. Lesion size increased with the degree of HC and was accompanied by increased collagen synthesis and smooth muscle cell (SMC) proliferation at each site. Amlodipine (5 mg/kg p.o.) inhibited lesion size by 50% (P < 0.01) at both sites in cholesterol-fed animals but not at angioplasty sites in animals on a normal diet. Local collagen synthesis was inhibited at both sites by amlodipine in the diet animals. The increase in HC was accompanied by a 1.7-fold increase in basal Ca2+ uptake in SMCs in the thoracic aorta, which was not altered by amlodipine, nifedipine, Ni2+, or La3+, revealing an uninhibitable calcium leak during atherogenesis. In culture, cholesterol enrichment increased SMC proliferation, collagen synthesis, and the secretion of a soluble SMC mitogen, which were inhibited by amlodipine (10(-9) M). Finally, in SMC membranes, amlodipine uniquely restored the cholesterol-expanded membrane bilayer width without any effect on membrane fluidity. This study establishes a causal role between serum HC and the development of spontaneous and angioplasty-induced lesions and the ability of amlodipine to disrupt this action by a novel remodelling action on the SMC membrane.

Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice

“…Theilmeier et al (5) described a sparse SMC population in postangioplasty atherosclerotic lesions in porcine coronary arteries, suggesting a negative effect of hypercholesterolemia on SMC proliferation. In a similar study, Kahn et al (6) observed a positive correlation between postangioplasty lesion size and blood cholesterol levels in the aorta of hypercholesterolemic rabbits. In the latter study, however, the relative proportions of SMCs and other cellular components of the lesion were not determined.…”

“…For instance, Theilmeier et al (5) showed that hypercholesterolemia decreased the population of SMCs in atheromatous lesions in postangioplasty porcine coronary arteries. In contrast, in a recent study, Kahn et al (6) observed accelerated angioplasty-induced intimal hyperplasia in aortas from hypercholesterolemic rabbits. In both studies, circulating levels of cholesterol were 9-and 18-fold higher than control levels, exceeding the pathophysiologic range of human hypercholesterolemia.…”

A membrane defect in the pathogenesis of the Smith-Lemli-Opitz syndrome

“…Third, cholesterol is essential for the synthesis of cell membranes, and it is the only sterol that mammals normally use in this capacity. In the membrane, it sets the levels of membrane fluidity, permeability, and, importantly, membrane width (24,25,34) appropriate for the specific membrane type (for width, plasma membrane . endoplasmic reticulum z Golgi .…”

“…Cell proliferation was assessed by measuring [ 3 H]thymidine uptake into DNA as described previously (34). Cells were grown to near confluence and incubated overnight with [ 3 H]thymidine.…”

“…Enrichment of the SLOS cell membranes with cholesterol was accomplished using cholesterol-rich liposomes as described previously (28,34). Cholesterol-rich liposomes were prepared by cosonication of cholesterol with egg phosphatidylcholine in a 2:1 molar ratio, followed by centrifugation, filter sterilization, and confirmation by gas-liquid chromatography and phospholipidphosphorus colorimetry before experimentation.…”