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1 surgery, Albert Einstein Medical Center, Philadelphia, PA, USA
2 Biochemistry, University of Pennsylvania Dental School, Philadelphia, PA, USA
3 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
4 Medicine, University of California Medical Center, Orange, CA, USA
5 Surgery, Thomas Jefferson University, Philadelphia, PA, USA
6 --, Elucida Research, Beverly, MA, USA
* To whom correspondence should be addressed. E-mail: Thomas.Tulenko{at}jefferson.edu.
Object: 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 (N), 0.5% or 2% cholesterol diets for 9 weeks 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 an increased collagen synthesis and SMC proliferation at each site. Amlodipine (5 mg/kg, p.o.) inhibited lesion size 50% (p<.01) at both sites in cholesterol-fed animals, but not at angioplasty sites in animals on 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 Ca++ uptake in SMC in the thoracic aorta which was not altered by amlodipine, nifedipine, Ni++ or La+++ 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). Lastly, 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 cell membrane.
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