Reduction of Serum Cholesterol Levels Alters Lesional Composition of Atherosclerotic Plaques

Abstract

We examined whether serum cholesterol reduction alters the lesional composition of atherosclerotic plaques. To reduce serum cholesterol levels, we gave pravastatin sodium, a 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, to mature Watanabe heritable hyperlipidemic rabbits, an LDL receptor-deficient animal model, for 48 weeks. Atherosclerotic lesions were immunohistochemically and conventionally stained and each lesional component area was measured by a color image analyzer. Compared with those of a placebo group, serum LDL cholesterol levels were reduced by 22% (P<.05). Data for atherosclerosis indicated a significant decrease in percent of surface lesion area (26% reduction) and in intimal thickening (30% reduction) in the abdominal aorta, as well as in coronary stenosis (29% reduction). Data for lesional composition indicated a significant decrease in the percent area of macrophage plus extracellular lipid deposits in aortic lesions (32% reduction) and coronary lesions (45% reduction). A significant increase was observed in the percent area of collagen in aortic lesions and in the percent area of smooth muscle cells in coronary lesions. The plaques seemed to become stable lesions as a result of pravastatin treatment. In conclusion, a long-term reduction of serum LDL cholesterol reduced lipid-related lesional components, in addition to suppressing the progression of established atherosclerosis.

Lipid Lowering by Diet Reduces Matrix Metalloproteinase Activity and Increases Collagen Content of Rabbit Atheroma

“…As in previous studies, we documented that lipid lowering decreased numbers of macrophages in experimental atheroma. 19,20 However, functional attributes of these and other lesional cells have not been investigated heretofore. The results presented here provide an experimental basis for understanding potential mechanisms for stabilization of atheromatous plaques.…”

“…However, the precise molecular and cellular mechanisms that might produce such "stabilization" of atheroma remain conjectural. The classic works of Armstrong et al 16,17 and Small et al, 18 as well as more recent investigations, 19,20 have suggested decreased macrophage number, decreased lipid content, and relative increase connective tissue during lipid lowering in animals. However, these previous studies have not generally addressed the biochemical and molecular aspects of the functions of lesional cells during lipid lowering.…”

Pravastatin Attenuates Cardiovascular Inflammatory and Proliferative Changes in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis by Its Cholesterol-Lowering Independent Actions.

“…For example, HMG-CoA reductase inhibitors such as pravastatin have been shown to inhibit chemotactic migration of monocytes (17) and neutrophils (18) in vitro. Treatment with pravastatin has been shown to reduce the number of monocytes infiltrated into atherosclerotic plaques (19,20) and to reduce metalloproteinase activity (21,22). Furthermore, pravastatin therapy appears to result in reductions in C-reactive protein levels and coronary events after acute myocardial infarctions in patients (23,24).…”

Genetically Modified Animal Models for Lipoprotein Research

“…In addition, simvastatin, a statin, did not decrease serum cholesterol levels in LDLR-KO mice and CETP(+/-)LDLR(-/-)mice, and increased serum cholesterol levels in apoE-KO mice at a dose of 30 mg/kg/day (Yin, 2012), although an extremely high dose of statins (0.168% in diet, 200-300 mg/kg/day) decreased serum cholesterol levels in LDLR-KO mice (Krause, 1998). In contrast, WHHL rabbits, an animal model of familial hypercholesterolemia, have played important roles in studies of the hypocholesterolemic effects and anti-atherosclerotic effects of statins (Shiomi, 1995;). The cholesterol-lowering effect of statins is mainly mediated by an increase in LDLR in liver.…”

“…Before the development of genetically modified animals, the Watanabe heritable hyperlipidemic (WHHL) rabbit, the first animal model for familial hypercholesterolemia, developed by Yoshio Watanabe in 1980 (Watanabe, 1980), helped to verify a low-density lipoprotein (LDL) receptor-pathway in vivo and to clarify lipoprotein metabolism in humans (Goldstein, 1983), in addition to the process by which atherosclerosis develops (Shiomi, 2009). Furthermore, WHHL rabbits have contributed to the development of hypocholesterolemic agents, statins, (Watanabe, 1981;Tsujita, 1986) and to clarifying anti-atherosclerotic effects (Watanabe, 1988;Shiomi, 1995;. In the present, WHHL rabbits were improved by selective breeding to produce the WHHLMI strain, which suffers from severe and vulnerable coronary atheromatous plaques and myocardial infarction due to coronary occlusion with progression of atherosclerotic plaques (Shiomi, 2003).…”