Characteristic change in local pulse wave velocity in different segments of the atherosclerotic aorta in KHC rabbits

BACKGROUND: Pulse wave velocity, conventionally determined between the carotid and femoral arteries, is a useful measure to estimate stiffness of the aorta. We investigated local pulse wave velocity (LPWV) in different segments in the aorta with relatively early-stage atherosclerosis in relation to the extent and severity of atherosclerotic lesions. METHODS: Pressure waves were recorded in eight aortic positions using two catheters with one or two micromanometers to determine LPWV in the ascending aorta, distal end of the aortic arch, proximal, middle, and distal thoracic aortas, and proximal, middle, and distal abdominal aortas in Kurosawa and Kusanagi-hypercholesterolemic (KHC) and normal rabbits aged 10 to 12 months. RESULTS: The LPWV in the KHC rabbit was greatest in the aortic arch, decreased almost to the normal level in the middle and distal thoracic aorta, increased in the proximal abdominal aorta, and showed almost identical change to that in the normal rabbit in the middle and distal abdominal aortic regions. There was significant difference in LPWV in the aortic arch, proximal thoracic, and proximal abdominal aortas between the two rabbit groups. The sclerotic lesion was prominent in the aortic arch, proximal thoracic aorta, and proximal abdominal aortas. The wall was severely thickened with abundant foam cells. The significant increase in LPWV would be mainly related to the increased wall thickness in these aortic regions. CONCLUSIONS: We can conclude that LPWV reflects well the distribution and severity of atherosclerotic lesion and the increased wall thickness in the local aortic region in which pulse waves were traveled.     

Distinct profiles of endothelial gene expression in hyperpermeable regions of the porcine aortic arch and thoracic aorta

Among the early events associated with atherosclerotic lesion development are increased macromolecular permeability of the endothelium and expression of genes that affect inflammation and oxidative state. The purpose of this study was to measure the expression of several atherosclerosis-related genes in endothelial cells scraped from arch and thoracic regions of the porcine aorta exhibiting elevated permeability. Aortae were collected from six swine that were exposed to circulating Evans blue dye (EBD), a marker of transendothelial albumin permeability. Endothelial cells were scraped from (1) white regions in the thoracic aorta, (2) light blue streaks and blue regions near ostia in the thoracic aorta, and (3) dark blue regions in the aortic arch. Expression levels of several genes were analyzed by real-time quantitative PCR. There were modest differences between the expression levels of several genes in cells from the light blue regions relative to those from white regions. In the dark blue regions, eNOS was drastically downregulated and MCP-1 was upregulated relative to their expression in both the white and light blue regions. The distinct levels of permeability and differences in gene expression profiles exhibited by cells from these different regions of the aorta may reflect corresponding differences in their hemodynamic environments.     

Quantification in vivo of increased LDL content and rate of LDL degradation in normal rabbit aorta occurring at sites susceptible to early atherosclerotic lesions

While the exact mechanisms that initiate atherosclerotic lesions are unknown, considerable evidence supports a role for low density lipoprotein (LDL). We investigated whether in the normal rabbit, LDL metabolism in areas of aorta that are destined to become lesioned during cholesterol feeding differed from the metabolism in adjacent lesion-resistant aorta. These studies took advantage of the predictable pattern of early atherosclerotic lesions in the cholesterol-fed rabbit. Early lesions occur diffusely in the aortic arch and ascending aorta and distal to branch orifices in the abdominal aorta and the descending thoracic aorta. Arterial rates of irreversible degradation of LDL and concentrations of intact LDL were measured in susceptible and resistant sites with homologous doubly labeled LDL. LDL was labeled directly with 131I and with 125I-tyramine cellobiose. The latter label provides a highly sensitive means to determine the sites and rates of lipoprotein degradation in vivo. The arterial concentration of intact LDL in the lesion-prone aortic arch was 3.12 +/- 0.45 micrograms LDL cholesterol/g (n = 14), 3.6 +/- 0.69 times that in the relatively lesion-resistant descending thoracic aorta (p less than 0.001). The rate of LDL degradation in the aortic arch was 3.14 +/- 0.41 micrograms LDL cholesterol/g/day, 2.14 +/- 0.24 times that in the descending thoracic aorta (p less than 0.001). In the abdominal aorta, the LDL (per gram wet weight) concentration and degradation rate (per square centimeter surface area) at branch sites exceeded that at nonbranch sites by 88 +/- 11% (p less than 0.001) and by 61 +/- 8% (p less than 0.001), respectively. These data provide evidence that in the normal rabbit, which does not develop atherosclerotic lesions, focal elevations of arterial LDL degradation rate and concentrations of intact LDL occur at sites that first develop atherosclerotic lesions in the hypercholesterolemic animal. These differences in LDL metabolism may be linked causally to the propensity to develop atherosclerotic lesions at these sites.     

Effect of aortic taper on patterns of blood flow and wall shear stress in rabbits: association with age

ObjectiveThe distribution of atherosclerotic lesions changes with age in human and rabbit aortas. We investigated if this can be explained by changes in patterns of blood flow and wall shear stress.MethodsThe luminal geometry of thoracic aortas from immature and mature rabbits was obtained by micro-CT of vascular corrosion casts. Blood flow was computed and average maps of wall shear stress were derived.ResultsThe branch anatomy of the aortic arch varied widely between animals. Wall shear was increased downstream and to a lesser extent upstream of intercostal branch ostia, and a stripe of high shear was located on the dorsal descending aortic wall. The stripe was associated with two vortices generated by aortic arch curvature; their persistence into the descending aorta depended on aortic taper and was more pronounced in mature geometries. These results were not sensitive to the modelling assumptions.ConclusionsBlood flow characteristics in the rabbit aorta were affected by the degree of taper, which tends to increase with age in the aortic arch and strengthens secondary flows into the descending aorta. Previously-observed lesion distributions correlated better with high than low shear, and age-related changes around branch ostia were not explained by the flow patterns.     

Meta-analysis of the effects of statin therapy on endothelial function in patients with diabetes mellitus

ObjectiveWe investigated the relationships between hemodynamics and differential plaque development at the aortic arch of apolipoprotein E (apoE)-null mice on 129S6/SvEvTac (129) and C57BL/6J (B6) genetic backgrounds.MethodsMean flow velocities at the ascending and descending aorta (mVAA and mVDA) were measured by Doppler ultrasound in wild type and apoE-null male mice at 3 and 9 months of age. Following dissection of the aortic arches, anatomical parameters and plaque areas were evaluated.ResultsArch plaques were five times bigger in 129-apoE than in B6-apoE mice at 3 months, and twice as large at 9 months. The geometric differences, namely larger vessel diameter in the B6 strain and broader inner curvature of the aortic arch in the 129 strain, were exaggerated in 9-month-old apoE-null mice. Cardiac output and heart rate under anesthesia were significantly higher in the B6 strain than in the 129 strain. The values of mVAA were similar in the two strains, while mVDA was lower in the 129 strain. However, there was a 129-apoE-specific reduction of flow velocities with age, and both mVAA and mVDA were significantly lower in 129-apoE than in B6-apoE mice at 9 months. The mean relative wall shear stress (rWSS) over the aortic arch in 129-apoE and B6-apoE mice were not different, but animals with lower mean rWSS had larger arch plaques within each strain.ConclusionsThe plaque formation in the arch of apoE-null mice is accompanied by strain-dependent changes in both arch geometry and hemodynamics. While arch plaque sizes negatively correlate with mean rWSS, additional factors are necessary to account for the strain differences in arch plaque development.     

Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.

The effects of trandolapril (0.25 mg/kg body wt per 48 hours) on aortic atherosclerosis were examined in the Watanabe heritable hyperlipidemic rabbit treated from 3 to 12 months of age. Trandolapril caused a significant decrease in atherosclerotic involvement of the intimal surface of total aorta from 56.3 +/- 5.0% in control Watanabe rabbits to 35.0 +/- 4.1% with treatment (p less than 0.01). The largest reductions were observed in descending thoracic aorta where 21.8 +/- 5.7% of intimal surface was involved in the trandolapril-treated animals versus 54.4 +/- 7.7% in the control group (p less than 0.01). Significant decreases also occurred in ascending aorta/arch and abdominal aortic segments. Cholesterol content of descending thoracic aorta was also significantly reduced in the trandolapril-treated rabbits. The atherosclerotic plaques in aorta from trandolapril-treated rabbits appeared to contain less foam cells and relatively greater amounts of connective tissue than those from control animals. These studies indicate that trandolapril inhibits aortic atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. The similarity in results between the current study and that using captopril suggests that the antiatherosclerotic action of trandolapril and captopril represents a class effect related to angiotensin converting enzyme inhibition.     

Imaging of vulnerable atherosclerotic plaques with FDG-microPET: no FDG accumulation

BACKGROUND: Non-invasive methods of evaluating atherosclerosis in humans and experimental animals are needed. Studies indicate that FDG-PET has a potential to detect vulnerable, inflamed atherosclerotic lesions. METHODS: Nine atherosclerotic apoE-deficient mice were PET scanned. Four to determine optimal timing for imaging, and five post mortem after 1h redistribution of FDG and again after sequential removal of the interscapular brown fat and the atherosclerotic aortic arch. Uptake in various tissues in fasting (n=13) and non-fasting (n=7) apoE-deficient mice, including atherosclerotic and non-atherosclerotic aorta, was measured. Finally, accelerated atherosclerosis was induced by carotid ligation (n=12), and FDG-uptake was measured. RESULTS: FDG accumulation initially thought to correspond to the atherosclerotic aortic arch was recorded. Removal of interscapular brown fat, but not atherosclerotic aortic arch, removed the signal. The aortic arch accumulated less FDG than the non-atherosclerotic thoracic aorta both in fasting (ratio 0.5, p=0.008) and non-fasting (ratio 0.33, p=0.02) conditions. Carotid atherosclerosis likewise failed to increase FDG-uptake compared to the non-ligated artery (ratio 1.03). CONCLUSION: Spontaneously developed advanced atherosclerotic lesions in aorta were, paradoxically, associated with reduced FDG uptake, and accelerated carotid atherosclerosis also failed to increase FDG-uptake. The results seriously question the potential of FDG-PET for imagining of advanced, vulnerable atherosclerotic lesions.     

Assessment of atherosclerotic lesions and distensibility of the thoracic aorta in familial hypercholesterolemia by biplane transesophageal echocardiography]

Atherosclerosis involving the thoracic aorta frequently occurs in patients with familial hypercholesterolemia (FH). In this study, we employed two-dimensional (2-D) transesophageal echocardiography (TEE: 5 MHz) to assess atherosclerotic lesions of the thoracic aorta in 9 patients with FH (47.8 +/- 10.3 yrs) and 11 age-matched normal control subjects. Biplane TEE probe (i.e., transverse or sagittal scan transducer) was used to permit direct imaging of the distal half of the ascending aorta. The atherosclerotic lesions were classified based on the severity of the aortic wall sclerosis as intimal thickening (I.), atheromatous plaque, (II.) and calcification (III.). In all of the patients with FH, atherosclerotic lesions of grade I. or greater were observed particularly in the aortic arch and descending aorta, while, lesions more severe than grade I. in the thoracic aorta were not observed in any of the control subjects. In 6 FH patients (67%), atherosclerotic lesions more severe than grade II. were frequently observed, which were more frequent in the aortic arch and descending aorta than in the ascending aorta.     

Is aortic dilatation an atherosclerosis-related process? Clinical,laboratory, and transesophageal echocardiographic correlates of thoracic aortic dimensions in the population with implications for thoracic aortic aneurysm formation

OBJECTIVES: The study determined, in a population-based setting, whether dilatation of the thoracic aorta is an atherosclerosis-related process. BACKGROUND: The role of atherosclerosis in thoracic aortic dilatation and aneurysm formation is poorly defined. METHODS: The dimensions of the thoracic aorta were measured with transesophageal echocardiography in 373 subjects participating in a population-based study (median age 66 years; 52% men). The associations between clinical and laboratory atherosclerosis risk factors, aortic atherosclerotic plaques, and aortic dimensions were examined. RESULTS: Age, male gender, and body surface area (BSA) jointly accounted for 41%, 31%, 38%, and 47% of the variability in diameters of the sinuses of Valsalva, ascending aorta, aortic arch, and descending aorta, respectively. Adjusting for age, gender, and BSA: 1) smoking was associated with a greater aortic arch diameter, and diastolic blood pressure and diabetes were each associated with a greater descending aorta diameter (p < 0.05); 2) atherosclerotic plaques in the descending aorta were associated with a greater descending aorta diameter (0.18 +/- 0.08-mm increase in diameter per 1-mm increase in plaque thickness; p = 0.02); and 3) minor negative associations were noted between atherosclerotic plaques and risk factors for atherosclerosis and the dimensions of the proximal thoracic aorta. Notably, atherosclerosis risk factors and plaque variables each accounted for <2% of the variability in aortic dimensions, adjusting for age, gender, and BSA. CONCLUSIONS: Age, gender, and BSA are major determinants of thoracic aortic dimensions. Atherosclerosis risk factors and aortic atherosclerotic plaques are weakly associated with distal aortic dilatation, suggesting that atherosclerosis plays a minor role in aortic dilatation in the population.     

Atherosclerotic enlargement of the human abdominal aorta

Aortic aneurysms usually develop in the atherosclerosis prone infrarenal abdominal aorta. To assess the role of atherosclerosis in aortic enlargement, we studied the relation between plaque formation and aortic size in 30 pressure-fixed male cadaver aortas (age 40-95 years, mean age 67 years). Morphometric analysis of transverse sections of the mid-thoracic and the mid-abdominal aortas included measurement of intimal plaque area, lumen area, plaque and media thicknesses. The area encompassed by the internal elastic lamina area (IEL area) was taken to be an index of aortic size. IEL area increased with age at both the thoracic (r=0.77, P<0.01) and abdominal (r=0.54, P<0.01) aortic levels. The aorta also enlarged with increasing plaque area at the thoracic (r=0.73, P<0.01) and abdominal (r=0.79, P<0.01) levels. Regression analysis of IEL area on age, body weight, height and plaque area revealed that the primary predictor of thoracic aortic size was age, whereas the primary predictor of abdominal aortic size was plaque area. Plaque thickness in the abdominal aorta was greater than in the thoracic aorta (P<0.01). Increased plaque area was associated with a significant decrease in media thickness in the abdominal aorta (r=-0.75, P<0.01) but not in the thoracic aorta. Aortas with relatively enlarged abdominal segments, i.e. those with a thoracic to abdominal ratio of <1.2 (n=13), were compared to those with a normal ratio (> or =1.2, n=17). Relatively large abdominal aortas had twofold greater plaque area (P<0.001), reduced medial thickness (P<0.05), fewer medial elastic lamellae (P<0.01) and greater mural tensile stress (P<0.05) than relatively normal abdominal aortas. We conclude that plaque formation in the infrarenal abdominal aorta in humans is associated with aortic enlargement and decreased media thickness. These changes may be predisposing factors for the preferential development of subsequent aneurysmal dilation in the abdominal aorta.     

Endothelial nitric oxide synthase activity in aorta of normocholesterolemic rabbits: regional variation and the effect of estrogen

OBJECTIVE: Several animal studies suggest that nitric oxide (NO) produced by the endothelium attenuates arterial cholesterol accumulation. In the present study we have asked the following questions: (1) is the regional variation in aortic cholesterol accumulation in hypercholesterolemic rabbits preceded by a regional variation in endothelial NO synthase (eNOS) activity in normocholesterolemic rabbits, and (2) is the antiatherogenic effect of estrogen in hypercholesterolemic rabbits preceded by a higher eNOS activity in normocholesterolemic rabbits. METHODS: The eNOS activity was determined by conversion of 14C-L-arginine to 14C-L-citrulline in freshly isolated endothelial cells of aorta in normocholesterolemic rabbits. In the regional variation study, 16 male and eight female rabbits were used. In the estrogen study, ovariectomized female rabbits were subcutaneously injected three times weekly with either 17beta-estradiol (n=7) or vehicle (n=7) for 18 weeks. RESULTS: In the regional variation study, the atherosclerosis prone aortic arch showed a significant lower eNOS activity than the more resistant abdominal aorta in both male (P<0.0001) and female (P<0.05) rabbits. In the estrogen study, the eNOS activity in the aortic arch and upper thoracic aorta was significantly higher in the estrogen than in the vehicle rabbits (P<0.05). In the lower thoracic aorta, however, the eNOS activity was the same. CONCLUSION: The findings suggest that a high NO production in the luminal endothelium of the arterial wall precedes a low cholesterol accumulation during a subsequent period of hypercholesterolemia.     

Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor-/- mice

Activated lymphocytes and mast cells have been detected in human atherosclerotic lesions. Interleukin-4 (IL-4) is a prominent cytokine released during the activation of both these cell types, and its mRNA has been detected in human and mouse atherosclerotic lesions. To define the effects of IL-4 on atherogenesis, bone marrow stem cells from either IL-4-/- or IL-4+/+ mice were transplanted into lethally irradiated female low density lipoprotein (LDL) receptor-/- mice. After an interval sufficient to allow engraftment, mice were placed on a diet containing 21% saturated fat, 1.25% cholesterol, and 0.5% cholate. Hematopoietic engraftment was confirmed by the presence of the LDL receptor gene in bone marrow cells. The effect on IL-4 depletion was confirmed by quantifying cytokine release from splenocytes of reconstituted mice. The deficiency of IL-4 in bone marrow-derived cells had no effect on serum cholesterol concentrations or on the distribution of cholesterol among lipoproteins. Atherosclerotic lesion formation was not changed in the aortic root. However, deficiency of IL-4 led to reduced lesion size in the arch (9.1 +/- 1.1% versus 2.8 +/- 0.8% of intimal area, P<0.001) and the thoracic aorta (1.2 +/- 0.2% versus 0.4 +/- 0.1%, P<0.002). Therefore, IL-4 deficiency reduced atherosclerotic lesion formation in a site-specific manner in female LDL receptor-/- mice fed a high-fat diet.     

Does shear stress modulate both plaque progression and regression in the thoracic aorta?: Human study using serial magnetic resonance imaging

OBJECTIVES: The purpose of this study was to investigate the role of shear stress (SS) in plaque regression. BACKGROUND: A condition favorable to the development of atherosclerotic lesions is low oscillating SS. In the descending thoracic aorta, the relationship between plaque distribution and SS has never been characterized. The regression of plaque as the result of lipid-lowering therapy is associated with reverse atherogenic mechanisms. Therefore, we investigated the role of SS in plaque regression. Magnetic resonance imaging (MRI) provides a unique opportunity to noninvasively study morphology and hemodynamics. METHODS: Cross-sectional images of atherosclerotic plaques in the descending thoracic aorta of 10 asymptomatic, hypercholesteremic patients were acquired at baseline and 24 months after starting lipid-lowering therapy by using a black-blood sequence on a 1.5-T clinical MRI system (5 mm x 780 microm x 780 microm). Average wall thickness (WT) was derived per quadrant. The aorta was subdivided in segments 2 cm in length starting 1 cm from the aortic arch. RESULTS: Average WT decreased with increasing distance from the arch (3.0 +/- 0.7 mm vs. 2.5 +/- 0.3 mm; p < 0.05) and showed a helical pattern from the proximal to distal segments. Phase-contrast MRI was performed in the thoracic aorta of eight healthy volunteers to derive typical average SS distribution. Shear stress predicted the location of WT (r(2) = 0.29, p < 0.05) but did not predict plaque regression. The best predictor of plaque regression was baseline WT. CONCLUSIONS: Our data showing an association between WT and average low SS locations support the role of local hemodynamics in the development of atherosclerotic lesions in descending thoracic aorta. Furthermore, SS does not seem to be the major predictor for plaque regression by lipid-lowering interventions. Therefore, our data suggest that other mechanisms are involved in the lipid-reversal mechanism.     

Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.

Accumulating evidence supports an association between Chlamydia pneumoniae infection and atherosclerosis. To determine whether there is a causal relationship, the effects of chronic infection with C. pneumoniae on the development of atherosclerosis in apolipoprotein E (apoE)-deficient mice were evaluated. Eight-week-old male apoE-deficient mice were inoculated intranasally with C. pneumoniae three times, at 8, 9, and 10 weeks of age. The combined area of atherosclerotic lesions in the lesser curvature of the aortic arch was measured en face by computer-assisted morphometry. The lesion area was 2.4-fold greater (P=.05) at 16 weeks of age and 1.6-fold greater (P=.05) at 20 weeks of age in infected mice than in control mice. There were no differences in total plasma cholesterol levels between groups. This study demonstrates that C. pneumoniae infection accelerates the progression of atherosclerosis in the aortic arch of apoE-deficient mice.     

Reduced in vitro repair in endothelial cells harvested from the intercostal ostia of porcine thoracic aorta

The ability of large-vessel endothelium to repair itself rapidly after injury is important in the maintenance of its barrier function and in limiting the development and progression of atherosclerosis. Because dysfunctional repair may be involved in the pathogenesis of some atherosclerotic plaques, including those at the ostia of aortic branches, linear mechanical denuding wounds were made in confluent monolayers of endothelial cells harvested by scraping from the flow divider, the upstream wall of the intercostal branch and unbranched regions in the thoracic aorta. The extent of wound closure was significantly lower in cells derived from either side of the intercostal branches, compared with cells from unbranched areas. The wound edge of cells harvested from the flow divider and its opposite wall closed by 22+/-0.084 microm and 22+/-1.3 microm, respectively, versus control, unbranched endothelial cells (30+/-2.2 microm) at 24 hours and by 48 hours, 48+/-3.4 microm and 47+/-3.6 microm compared with control (61+/-3.4 microm). Extent of wound closure in cells harvested by scraping from unbranched regions was comparable with collagenase-harvested endothelial cells at 24 and 48 hours. Distribution of F-actin microfilaments, tubulin and centrosomes have been shown to be disrupted at the wound edge in poorly migrating cells. In our study, however, no differences were observed in cytoskeletal distribution between cells from branched, unbranched and control areas. Thus, aortic endothelial cells from the intercostal branch region show a reduced ability to repair wounds compared with cells harvested from unbranched aorta. The mechanism for this difference is currently unknown.     

Evaluation of morphological changes of the atherosclerotic aorta by enhanced computed tomography.

Enhanced and non-enhanced computed tomography (CT) were performed in 405 subjects (222 men; 183 women; mean age 57 years). Intimal atherosclerotic changes of the aorta were quantified by enhanced CT, revealing the atheromatous intima to be projecting and thick-walled, while non-enhanced CT demonstrated aortic calcification. We measured the degree of aortic intimal changes at various segments of the aorta. In 224 cases, CT was performed from the aortic root to the bifurcation of the abdominal aorta. Intimal changes were found predominantly at the aortic arch, the middle descending thoracic and the infrarenal abdominal aorta. As for the intimal changes, aortic calcification and aortic pulse wave velocity were significant atherosclerotic characteristics. The aortic diameter did not show a significant association with intimal change. Among the various atherosclerotic risk factors, intimal change was significantly associated with age, systolic blood pressure, serum total cholesterol and diabetes mellitus, whereas gender, diastolic blood pressure, relative weight and cigarette use were not significantly related. For coronary artery disease and arteriosclerosis obliterans, aortic intimal changes constituted a significant atherosclerotic feature. In cerebrovascular disease, however, aortic intimal change did not play a significant role.     

Aortic recruitment of blood lymphocytes is most pronounced in early stages of lesion formation in apolipoprotein-E-deficient mice

Lymphocyte accumulation in the arterial intima affects development of atherosclerotic lesions. We studied the kinetics of lymphocyte accumulation in the arterial wall by injecting lymphocytes from male LacZ transgenic mice into female apolipoprotein-E-deficient mice. Recipient mouse aortas were removed and separated into lesioned and non-lesioned parts 2, 24, 48, or 72 h later. The accumulation of donor lymphocytes was quantified with real-time PCR of donor lymphocyte-specific genes. The accumulation of lymphocytes in the lesioned parts of aorta decreased with increasing lesion severity (r=-0.74, P=0.0005, n=18). Moreover, the accumulation of lymphocytes in the lesioned part of aorta was larger (392+/-108%, P=0.016) compared with the accumulation in the non-lesioned part in mice with mild atherosclerosis, whereas it was smaller (58+/-19%, P<0.01) compared with the accumulation in the non-lesioned part in mice with severe atherosclerosis. The results suggest that aortic recruitment of blood lymphocytes is most pronounced in early stages of lesion formation.     

Propagermanium reduces atherosclerosis in apolipoprotein E knockout mice via inhibition of macrophage infiltration

Monocyte chemoattractant protein-1 (MCP-1), which binds to C-C chemokine receptor 2, has been implicated as the primary source of monocyte chemoattractant function in the early stages of atherosclerosis. Recently, propagermanium, a drug used clinically for the treatment of chronic hepatitis in Japan, has been shown to inhibit C-C chemokine receptor 2 function and suppress monocyte/macrophage infiltration in vitro and in vivo. Given the importance of monocyte infiltration in atherogenesis, the inhibition of it by propagermanium might prevent atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were fed an atherogenic high cholesterol diet with or without 0.005% propagermanium for 8 or 12 weeks. Although the plasma lipid levels were unchanged by the drug treatment, atherosclerotic lesion area in the aortic root was reduced by 50% in the drug-treated apoE-KO mice compared with the nontreated apoE-KO mice after 8 weeks of cholesterol feeding (0.62+/-0.12 versus 1.27+/-0.07 mm2, respectively; P<0.01). Moreover, the accumulation of macrophages in the lesions was markedly reduced in the drug-treated group (macrophage positive area, 0.23+/-0.06 mm2 [drug-treated group] versus 0.67+/-0.07 mm2 [control group]; P<0.01). After 12 weeks of cholesterol feeding, atherosclerotic lesion formation in the aortic root and in the descending thoracic aorta was significantly reduced in the drug-treated group. Inhibition of macrophage infiltration by propagermanium prevented the formation of atherosclerotic lesions in apoE-KO mice. This drug may serve as a therapeutic tool for the treatment of atherosclerosis.     

Progression of induced aortic atherosclerosis in rabbits fed a high cholesterol diet

In this study we have evaluated the progression of atheromatosis in aortic arch, thoracic aorta and abdominal aorta in rabbits fed a high cholesterol diet. The aortic atheromatosis decreased progressively from the aortic arch to the abdominal aorta after 6 months of high cholesterol diet. It is possible that a different segmental resistance to hypercholesterolemic damage may be involved in the cranio caudal progression of atheromatosis in rabbits.     

Aorta of ApoE-deficient mice responds to atherogenic stimuli by a prelesional increase and subsequent decrease in the expression of antioxidant enzymes

Oxidative stress has been implicated in the development of atherosclerotic lesions. We evaluated the relationship between extent of atherosclerotic lesion formation and vascular expression of pro- and antioxidant enzymes in apoE-deficient mice. On normal chow, these mice showed elevated serum cholesterol levels (7.5- to 9.5-fold), and age-dependent, spontaneous development of all stages of atherosclerotic lesions, starting at the age of 12 weeks. RNA was extracted from the aortic arch and descending aorta, and mRNA expression of pro- and antioxidant enzymes was measured with real-time PCR. Local infiltration of monocytes/macrophages, reflected by increased vascular expression of CD68 mRNA (>10-fold), indicated that the arch was more susceptible than the descending aorta. The expression of catalase-1 and various isoforms of superoxide dismutase, glutathione peroxidase, and glutathione S-transferase alpha was significantly increased in the aortic arch, but not in the descending aorta, in the period preceding lesion formation (age 6 to 12 weeks). These expression levels were 1.5 to 5 times higher than in age-matched wild-type animals. Remarkably, there was an inverse relationship between extent of lesion formation and the mRNA levels of antioxidant enzymes, most of which started to decline after 12 weeks, as lesions developed. In contrast, inducible nitric oxide synthase expression increased 4-fold in the aortic arch over the course of the disease. Our results suggest that the arterial wall responds to increased serum levels of atherogenic lipoproteins by stimulating expression of antioxidant enzymes. The observed co-ordinate decline in expression of many of these protective systems may greatly accelerate the development of atherosclerosis.