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

Abstract

Two month old C57BL/6 mice were placed on three different diets: 1) normal diet (NC; 0.025% cholesterol), 2) hypercholesterolemic Western-type diet (HC-W; 0.2% cholesterol), and 3) hypercholesterolemic Paigen-type diet (HC-P; 1.25% cholesterol plus 0.5% cholic acid). At 6 months of age, the animals underwent ligation of the left carotid artery and were randomly assigned to vehicle (PBS, subcutaneous) or angiotensin II (Ang II; 1.4 mg/kg/ day, subcutaneous) treatment for 4 weeks. Low density lipoprotein-cholesterol levels were similarly increased in both HC diets (NC, 4 6 3 mg/dl; HC-W, 123 6 17 mg/dl; HC-P, 160 6 14 mg/dl). However, the levels of high density lipoprotein-cholesterol (HDL-C) were reduced only in animals fed the HC-P diet (NC, 82 6 6 mg/dl; HC-W, 79 6 7 mg/dl; HC-P, 58 6 7 mg/dl). In Ang II-treated mice, carotid artery ligation induced intimal smooth muscle cell proliferation to a similar extent in NC-and HP-W-fed animals. However, a significantly larger intimal area developed in ligated vessels from Ang II-treated mice fed the HC-P diet (3.6-fold higher than in Ang II-treated NC mice). Together, these results show the accelerating effect of mild hypercholesterolemia, reduced HDL-C levels, and Ang II on intimal hyperplasia after carotid artery ligation in mice. Proliferation of smooth muscle cell (SMCs) and migration into the intima is the hallmark of restenosis after vascular interventions (angioplasty, stent or vein graft placement) (1-3) and an important feature of preatherosclerotic lesions (4). It is well established that hypercholesterolemia accelerates atherosclerosis development; however, studies addressing the effect of circulating cholesterol on intimal SMC proliferation have yielded conflicting results. 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. Additionally, the concomitant development of spontaneous atheromatous plaque found in these studies adds another important level of interaction between macrophage/foam cell-derived mediators and SMC proliferation (7).In addition to changes in hemodynamic forces (e.g., low shear stress) (8) as predisposing factors for intimal hyperplasia development, locally produced neurohumoral mediators, particularly angiotensin II (Ang II) (9), may be equally important in determining such predisposition. Increased vascular levels of Ang II and the expression of its AT1 receptors were found in intimal SMCs of aortas from aging nonhuman primates (10) and in in-stent restenotic lesions of human coronary arteries (11). More importantly, in vitro studies showing synergism between lipoproteins and Ang II in inducing...

The Effects of Cinnamomum zeylanicum on Lipid Profiles and Histology Via Up-Regulation of LDL Receptor Gene Expression in Hamsters Fed a High Cholesterol Diet

“…The findings in this study showed no changes in AST and ALT levels in the serum following higher doses of CZ consumption, indicating no harmful effects on the liver. However, da Cunha V et al's study indicated a reduction in HDL-c levels lower than the baseline (normal group); according to our experiments, HDL-c levels in hypercholesterolemic animals was higher than those of the normal group, and hence the results of our study were different (44).…”

Mechanisms of Intimal Hyperplasia Learned from a Murine Carotid Artery Ligation Model

“…CAL model further proved that hypercholesterolemia accelerated not only the development of neointimal lesion but also the vulnerability of atherosclerotic plaque. We have shown that the hypercholesterolaemic Paigen-type diet significantly increased CAL-induced intimal hyperplasia in C57 Black/6J mice treated with Ang II [10]. Ivan et al further reported that a hypercholesterolaemic diet not only enhanced CAL-induced neointimal hyperplasia, but also increased the macrophage area and metalloproteinase (MMP)-9 activity in intima in apolipoprotein E (apoE) deficient mice, a sign of increase in the vulnerability of atherosclerotic plaque [12].…”

“…This characteristic difference in the vascular remodeling in a different region of the carotid artery has been utilized in different studies. For example, Kawashima tions from segments close to the ligation site, where the neointimal lesion is severe, which is good for determining the inhibitory effect of endothelial nitric oxide synthase (eNOS) overexpression on the neointimal formation [9], while we chose middle portion of the carotid artery where the neointimal lesion is mild, which is good for detecting the enhancing effect of hypercholesterolaemia and angiotensin II (Ang II) [10] or eNOS deficiency [11] on neointimal development.…”

Expression of Endothelial Lipase Correlates with the Size of Neointima in a Murine Model of Vascular Remodeling

“…In addition, various inflammatory stimuli activate and induce the abnormal proliferation and migration of SMC, which play a central role in the formation of neointima 2) . High-density lipoprotein-cholesterol (HDL-C) has a protective role in the formation of vascular remodeling as well as atherosclerosis 5) . The anti-atherogenic actions of HDL are principally attributable to its function in the reverse cholesterol transport system.…”

“…For primary culture of aortic SMC of ELTg (ELTg-SMC), ELKO (ELKO-SMC), and WT mice (WT-SMC), the mice were euthanized with an overdose of pentobarbital (150 μg/g) plus buprenorphine (3 μg/g). Mouse aortic SMC were isolated from these mice by enzymatic dissociation, as described previously 5) . SMC were seeded at a density of 3000 cells/well in a 96-well plate.…”