Development of atherosclerotic lesions in cholesterol-loaded rabbits.
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To examine both of the target vessels and the optimal time of their endothelial denudation to study vascular restenosis after balloon injury in cholesterol-loaded rabbits, we made 36 atherosclerotic rabbits by feeding a hypercholesterol diet, and histologically examined the onset time and the development of atherosclerosis. Atheromatous changes were observed first after the 5th week in the thoracic aorta from the start of the diet, and then extended to the abdominal aorta, coronary artery with time. The atherosclerotic lesions in the thoracic aorta and the proximal portion of the coronary artery showed high-grade concentric intimal thickening with luminal stenosis. The abdominal aortic lesion mildly progressed. In the renal, carotid and femoral arteries, in contrast, slight atheroscleromatous changes developed during the diet period. These results suggest that the thoracic and abdominal aortas and the coronary artery would be suitable as target vessels to study vascular restenosis after balloon injury, and the endothelial denudation of these vessels should be performed between the 8th and 15th week in this diet protocol for an accurate analysis. (+info)
2-Isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195) treatment inhibits the development of intimal thickening after balloon injury of rat carotid artery: role of glycoxidation and lipoxidation reactions in vascular tissue damage.
(18/6134)
We have pursued the hypothesis that the carbonyl modification of proteins by glycoxidation and lipoxidation reactions plays a role in atherogenesis. Human atherosclerotic tissues with fatty streaks and uremic arteriosclerotic tissues were examined, with specific antibodies, to detect protein adducts formed with carbonyl compounds by glycoxidation or lipoxidation reactions, i.e. advanced glycation end products (AGEs) or glycoxidation products, such as carboxymethyllysine (CML) and pentosidine, and lipoxidation products, such as malondialdehyde (MDA)-lysine and 4-hydroxy-nonenal (HNE)-protein adduct. All the four adducts were identified in the proliferative intima and in macrophage-rich fatty streaks. If the carbonyl modification is not a mere result but is a contributor to atherogenesis, inhibition of glycoxidation and lipoxidation reactions might prevent vascular tissue damage. We tested this hypothesis in rats following balloon injury of their carotid arteries, a model exhibiting a remarkable intimal thickening, which are stained positive for all the four adducts. Oral administration of 2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanili de (OPB-9195), an inhibitor of both glycoxidation and lipoxidation reactions, in rats following balloon injury effectively prevented the intimal thickening. These data suggest a role for the carbonyl modification of proteins by glycoxidation and lipoxidation reactions in most, if not all, types of vascular tissue damage ('carbonyl stress'), and the usefulness of inhibitors of carbonyl reactions for the treatment of vascular tissue damage. (+info)
Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis.
(19/6134)
BACKGROUND: Exposure to risk factors such as hypertension or hypercholesterolemia decreases the bioavailability of endothelium-derived nitric oxide (NO) and impairs endothelium-dependent vasodilation. Recently, a circulating endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), has been detected in human plasma. The purpose of this study was to examine the relationship between plasma ADMA and atherosclerosis in humans. METHODS AND RESULTS: Subjects (n=116; age, 52+/-1 years; male:female ratio, 100:16) underwent a complete history and physical examination, determination of serum chemistries and ADMA levels, and duplex scanning of the carotid arteries. These individuals had no symptoms of coronary or peripheral artery disease and were taking no medications. Univariate and multivariate analyses revealed that plasma levels of ADMA were positively correlated with age (P<0.0001), mean arterial pressure (P<0.0001), and Sigma glucose (an index of glucose tolerance) (P=0.0006). Most intriguingly, stepwise regression analysis revealed that plasma ADMA levels were significantly correlated to the intima-media thickness of the carotid artery (as measured by high-resolution ultrasonography). CONCLUSIONS: This study reveals that plasma ADMA levels are positively correlated with risk factors for atherosclerosis. Furthermore, plasma ADMA level is significantly correlated with carotid intima-media thickness. Our results suggest that this endogenous antagonist of NO synthase may be a marker of atherosclerosis. (+info)
Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice.
(20/6134)
BACKGROUND: Iron deposition is evident in human atherosclerotic lesions, suggesting that iron may play a role in the development of atherosclerosis. To test this idea, the correlation between the extent of iron deposition and the severity of atherosclerosis in apolipoprotein E (apoE)-deficient mice was investigated. Furthermore, the effect of a low-iron diet on the progression of atherosclerotic lesions in these animals was evaluated. METHODS AND RESULTS: Iron deposition in tissues of apoE-deficient mice was examined by Perls' staining method. The results clearly demonstrated that iron deposits are present in atherosclerotic lesions and tissue sections of heart and liver in an age-dependent manner. When the young mice received a low-iron diet for 3 months, the hematocrit, serum iron, hemoglobin, and cholesterol concentrations were not significantly altered compared with those of littermates placed on a chow diet. However, the serum ferritin level of animals in the iron-restricted group was 27% to 30% lower than that of the control group in either sex. Furthermore, the lipoproteins isolated from the iron-restricted group exhibited greater resistance to copper-induced oxidation. Histological examination revealed that atherosclerotic lesions developed in mice fed a low-iron diet were significantly smaller than those found in control littermates. Likewise, the iron deposition as well as tissue iron content was much less in aortic tissues of the iron-restricted animals. Circulating autoantibodies to oxidized LDL and immunostains for epitopes of malondialdehyde-modified LDL detected on lesions were also significantly lower in mice fed a low-iron diet. CONCLUSIONS: Iron deposition is closely associated with the progression of atherosclerosis in apoE-deficient mice. Restriction in dietary iron intake leads to significant inhibition of lesion formation in these animals. These results suggest that the beneficial effect of a low-iron diet may be mediated, at least in part, by the reduction of iron deposition as well as LDL oxidation in vascular lesions. (+info)
Regression of atherosclerosis: role of nitric oxide and apoptosis.
(21/6134)
BACKGROUND: We have recently found that administration of L-arginine to hypercholesterolemic rabbits induces regression of preexisting lesions. Others have previously shown that activation of the L-arginine/nitric oxide (NO) synthase pathway can induce apoptosis of vascular cells in vitro. Accordingly, the current study was designed to determine if dietary supplementation of L-arginine induces apoptosis of intimal lesions and if this effect is mediated through the NO synthase pathway. METHODS AND RESULTS: Male New Zealand White rabbits were fed a 0.5% cholesterol diet for 10 weeks and subsequently placed on 2.5% L-arginine HCl in the drinking water, and the cholesterol diet was continued for 2 weeks, at which time the aortas were harvested for histological studies. L-Arginine treatment increased the number of apoptotic cells (largely macrophages) in the intimal lesions by 3-fold (11.9+/-3.9 vs 3.9+/-1. 4 apoptotic cells/mm2, P<0.01). In subsequent studies, aortas were harvested for ex vivo studies. Aortic segments were incubated in cell culture medium for 4 to 24 hours with modulators of the NO synthase pathway. The tissues were then collected for histological studies and the conditioned medium collected for measurement of nitrogen oxides by chemiluminescence. Addition of sodium nitroprusside (10(-5) mol/L) to the medium caused a time-dependent increase in apoptosis of vascular cells (largely macrophages) in the intimal lesion. L-Arginine (10(-3) mol/L) had an identical effect on apoptosis, which was associated with an increase in nitrogen oxides released into the medium. These effects were not mimicked by D-arginine, and they were antagonized by the NO synthase inhibitor L-nitro-arginine (10(-4) mol/L). The effect of L-arginine was not influenced by an antagonist of cGMP-dependent protein kinase, nor was the effect mimicked by the agonist of protein kinase G or 8-BR cGMP. CONCLUSIONS: These results indicate that supplemental L-arginine induces apoptosis of macrophages in intimal lesions by its metabolism to NO, which acts through a cGMP-independent pathway. These studies are consistent with our previous observation that supplementation of dietary arginine induces regression of atheroma in this animal model. These studies provide a rationale for further investigation of the therapeutic potential of manipulating the NO synthase pathway in atherosclerosis. (+info)
Prevalence of true vein graft aneurysms: implications for aneurysm pathogenesis.
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BACKGROUND: Circumstantial evidence suggests that arterial aneurysms have a different cause than atherosclerosis and may form part of a generalized dilating diathesis. The aim of this study was to compare the rates of spontaneous aneurysm formation in vein grafts performed either for popliteal aneurysms or for occlusive disease. The hypothesis was that if arterial aneurysms form a part of a systemic process, then the rates of vein graft aneurysms should be higher for patients with popliteal aneurysms than for patients with lower limb ischemia caused by atherosclerosis. METHODS: Infrainguinal vein grafting procedures performed from 1990 to 1995 were entered into a prospective audit and graft surveillance program. Aneurysmal change was defined as a focal increase in the graft diameter of 1.5 cm or greater, excluding false aneurysms and dilatations after graft angioplasty. RESULTS: During the study period, 221 grafting procedures were performed in 200 patients with occlusive disease and 24 grafting procedures were performed in 21 patients with popliteal aneurysms. Graft surveillance revealed spontaneous aneurysm formation in 10 of the 24 bypass grafts (42%) for popliteal aneurysms but in only 4 of the 221 grafting procedures (2%) that were performed for chronic lower limb ischemia. CONCLUSION: This study provides further evidence that aneurysmal disease is a systemic process, and this finding has clinical implications for the treatment of popliteal aneurysms. (+info)
Plaque area increase and vascular remodeling contribute to lumen area change after percutaneous transluminal angioplasty of the femoropopliteal artery: an intravascular ultrasound study.
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OBJECTIVE: The aim of the study was to assess the change in lumen area (LA), plaque area (PLA), and vessel area (VA) after percutaneous transluminal angioplasty (PTA) of the femoropopliteal artery. METHODS: This was a prospective study. Twenty patients were studied with intravascular ultrasound (IVUS) immediately after PTA and at follow-up examination. Multiple corresponding IVUS cross-sections were analyzed at the segments that were dilated by PTA (ie, treated sites; n = 168), including the most stenotic site (n = 20) and the nondilated segments (ie, reference sites; n = 77). RESULTS: At follow-up examination, both the PLA increase (13%) and the VA decrease (9%) resulted in a significant LA decrease (43%) at the most stenotic sites (P =.001). At the treated sites, the LA decrease (15%) was smaller and was caused by the PLA increase (15%). At the reference sites, the PLA increase (15%) and the VA increase (6%) resulted in a slight LA decrease (3%). An analysis of the IVUS cross-sections that were grouped according to LA change (difference >/=10%) revealed a similar PLA increase in all the groups: the type of vascular remodeling (VA decrease, no change, or increase) determined the LA change. At the treated sites, the LA change and the VA change correlated closely (r = 0.77, P <.001). At the treated sites, significantly more PLA increase was seen in the IVUS cross-sections that showed hard lesion or media rupture (P <.05). No relationship was found between the presence of dissection and the quantitative changes. CONCLUSION: At the most stenotic sites, lumen narrowing was caused by plaque increase and vessel shrinkage. Both the treated sites and the reference sites showed a significant PLA increase: the type of vascular remodeling determined the LA change at follow-up examination. The extent of the PLA increase was significantly larger in the IVUS cross-sections that showed hard lesion or media rupture. (+info)
Effect and outcome of balloon angioplasty and stenting of the iliac arteries evaluated by intravascular ultrasound.
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OBJECTIVES: To document the mechanism of percutaneous transluminal angioplasty (PTA) and stenting of the iliac arteries, and to relate the effect to patency. MATERIALS AND METHODS: Thirty-seven stenotic iliac arteries were examined by intravascular ultrasound (IVUS) and arteriography before and after PTA, and after stent deployment (n = 16). The patients were followed prospectively by duplex scanning at 3, 6, 12, 18 and 24 months after the intervention. RESULTS: The effect of PTA was established by both compression and stretching with the major contribution arising from stretching. There were differences in the effect of PTA dependent on plaque morphology: in homogeneous eccentric lesions, stretching contributed significantly more than compression to the luminal gain, while stretching and compression contributed equally in concentric or heterogeneous plaques. Stenting of the arteries had no effect on the free luminal area as measured by IVUS. The primary 1-year patency rate was 72%. The patency was related to the free luminal area and diameter and the heterogenicity of the plaque as evaluated by IVUS. The arteriographic measurements did not have any predictive value. CONCLUSION: IVUS was able to document the effect of PTA and stenting in the iliac arteries, and predict the outcome. The luminal gain and reduction in degree of stenosis seemed to be accomplished primarily by stretching of the arteries and to a lesser extent by plaque compression. Stenting did not change the IVUS measurements. Patency was related to the size of the free lumen and the heterogenicity of the plaque. (+info)