bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of serum lipid and apolipoprotein concentrations to predict extent of diet-induced atherosclerotic lesions in aortas and coronary arteries and to demonstrate regression of lesions in individual rhesus monkeys.
Authors: Eggen D A , Bhattacharyya A K , Strong J P , Newman W P , Guzman M A , Restrepo C
Published: June 2011

In most studies, the assessment of lesion "regression" is based on comparisons of group means between the "progression" and regression groups. This comparison depends on the assumption that the extent and distribution of lesions produced by the end of the lesion-induction period in the regression animals are equal to those observed in the progression group. To determine whether significant regression of lesions occurs in an individual regression animal, it is necessary to obtain a measure of the lesions produced in these animals at the end of the lesion-induction period. We achieved this goal by developing models using multiple stepwise regression analysis that related steady-state serum cholesterol and apolipoprotein B and A-I concentrations measured during a lesion-induction period in 27 rhesus monkeys fed an atherogenic high-saturated-fat/high-cholesterol diet for 2 years. The models were developed to estimate the percent of intimal surface with lesions, the esterified cholesterol content (micrograms/cm2) for the artery segments, and three histomorphometric measures (mean intimal thickness, mean maximal intimal thickness, and mean percent stenosis) for the coronary arteries. In these models, multiple R2 ranged from 0.42 to 0.74 for the aortas and peripheral arteries, indicating that approximately one half to three fourths of the variance in lesions was accounted for. For the three histomorphometric measures in coronary arteries, however, the multiple R2 was 0.27 or 0.28, indicating that only approximately one fourth of the variance in lesions was accounted for.(ABSTRACT TRUNCATED AT 250 WORDS)
Endogenous sex hormones, high density lipoprotein cholesterol, and other lipoprotein fractions in men.
Authors: Khaw K T , Barrett-Connor E
Published: June 2011

At least some of the large preponderance for coronary heart disease in men has been attributed to differences in lipid and lipoprotein levels; notably, high density lipoprotein cholesterol (HDL-C), a protective factor, is higher in women. The sex differences in lipid levels have been postulated to be related to differences in sex hormones. In a southern California cohort of 391 men aged 30-79 years, HDL-C levels were positively correlated and very low density lipoprotein cholesterol (VLDL-C) levels were inversely correlated with testosterone levels independently of age, body mass index, physical exercise, smoking, and alcohol intake. Mean HDL-C levels were 12% higher and VLDL-C levels were 40% lower in the highest compared with the lowest quartile of testosterone level. Low density lipoprotein cholesterol levels were positively related to estrone, estradiol, and androstenedione levels. It is premature to attribute the sex differential in lipid cardiovascular risk profiles to higher levels of testosterone per se in men, since testosterone levels are favorably associated with cardiovascular risk while estrogen levels have the converse relation in men. The differing effects and interactions of specific endogenous sex hormones in men and women require further elucidation.
Hypolipidemic effect of beta, beta'-tetramethyl hexadecanedioic acid (MEDICA 16) in hyperlipidemic JCR:LA-corpulent rats.
Authors: Russell J C , Dolphin P J , Hameed M , Stewart B , Koeslag D G , Rose-Kahn G , Bar-Tana J
Published: June 2011

Short-term treatment of male and female obese JCR:LA-corpulent rats with beta,beta'-tetramethyl hexadecanedioic acid (MEDICA 16) resulted in a marked decrease (as much as 80%) in plasma triglyceride values, with a concomitant decrease in the highly elevated very low density lipoprotein (VLDL) levels of the corpulent rat. There were modest decreases in cholesterol levels and increases in low density lipoprotein and high density lipoprotein lipids. The concentrations of apolipoproteins C-II and C-III were decreased in both the whole-serum and the VLDL fractions. Food consumption, rate of weight gain, fasting insulin levels, and the integrated insulin response to an intravenous glucose load remained unaffected. The decrease in plasma VLDL may be accounted for by inhibition of liver long-chain fatty acid synthesis at the level of ATP citrate lyase, with a concomitant reduction of VLDL triglyceride production by the liver. This decrease in plasma VLDL production was accompanied by a twofold to threefold increase in the triglyceride and cholesterol components of the low density lipoprotein and high density lipoprotein fractions, together with a twofold to fourfold decrease in plasma apolipoprotein, indicating that activation of plasma VLDL catabolism may further account for the overall hypolipidemic effect induced by MEDICA 16. The overall hypolipidemic effect of MEDICA 16 may be expected to inhibit the spontaneous atherogenic sequelae induced in the corpulent rat by severe VLDL hyperlipidemia.
Immunohistochemical detection of macrophages and T lymphocytes in atherosclerotic lesions of cholesterol-fed rabbits.
Authors: Hansson G K , Seifert P S , Olsson G , Bondjers G
Published: June 2011

Human atherosclerotic plaques contain significant numbers of T lymphocytes and monocyte-derived macrophages. Cytokines released from activated T lymphocytes induce aberrant expression of major histocompatibility complex class II (Ia) antigens by vascular smooth muscle cells and may also regulate cell proliferation and metabolism in the vessel wall. We have analyzed the arteries of cholesterol-fed rabbits to study the sequence of lymphocyte and monocyte entry into the forming atherosclerotic lesion. Rabbits were fed 0.3% cholesterol for 1-10 weeks, and monoclonal antibodies to rabbit leukocyte differentiation antigens and Ia antigen were applied to sections of the aorta. Monocytes were already observed 1 week after initiation of cholesterol feeding, and they accumulated in the intima, where they formed the bulk of the foam cell-rich lesion. T lymphocytes also adhered to the aortic surface from 1 week onward, and also accumulated in the lesion, although in lower proportions than did monocytes. In 10-week lesions, approximately 6% of cells expressed the T-lymphocyte marker L11/135. Ia antigen expression was frequent throughout the lesion in all phases of its development, and most of the Ia-expressing cells could be identified as monocyte-derived macrophages. These data indicate that the cholesterol-fed rabbit is a useful model for studying the role of monocytes and T lymphocytes in atherosclerosis.
Variable effects of different corticosteroids on plasma lipids, apolipoproteins, and hepatic apolipoprotein mRNA levels in rats.
Authors: Staels B , van Tol A , Chan L , Verhoeven G , Auwerx J
Published: June 2011

Treatment of male rats with hydrocortisone provoked a dose- and time-dependent decrease in plasma cholesterol concentration without a change in plasma triglyceride levels. In contrast, administration of triamcinolone and dexamethasone at equipotent glucocorticoid doses increased plasma cholesterol and triglyceride levels, respectively. Small effects on apolipoprotein E (apo E) and apo B mRNA levels were observed, but all corticosteroids increased apo A-I and apo A-IV mRNA and decreased apo A-II mRNA levels in the liver. Triamcinolone and dexamethasone, however, were three times more potent in stimulating hepatic apo A-IV gene expression than was hydrocortisone, whereas liver apo A-I and apo A-II mRNA levels were altered to a similar extent by all corticosteroids. Plasma apo A-I and apo B concentrations always varied in a similar fashion with their respective liver mRNA levels after administration of the distinct corticoids. For apo A-IV and apo E, discrepancies between plasma and liver mRNA levels after administration of the different steroids, however, point to additional regulatory effects on plasma apolipoprotein levels. We conclude that 1) in contrast to plasma apo A-I and apo B, alterations in plasma lipid, apo A-IV, and apo E levels depend on the type of corticosteroid used; and 2) glucocorticoids have a differential effect on hepatic mRNA levels of apo A-I and apo A-IV on the one hand and apo A-II on the other hand, an effect that may be of consequence in the process of reverse cholesterol transport.
Abnormal processing of Golgi elements and lysosomes in Tangier disease.
Authors: Robenek H , Schmitz G
Published: June 2011

It has been demonstrated that the cellular defect in Tangier disease is associated with morphological abnormalities in the lysosomal compartment and in the Golgi apparatus of mononuclear phagocytes (MNPs) after lipid loading by exposure to acetylated low density lipoproteins (acetyl-LDLs). On exposure to acetyl-LDL, Tangier MNPs accumulate two unusual types of vacuoles that were not observed in control MNPs. The electron-lucent type I vacuoles are round or ovoid, form aggregates, and are filled with fine flocculent or fibrillar material. Type II vacuoles are filled with more electron-dense material, are larger, and contain scrolls and lamellae with varying degrees of electron opacity. By immunoelectron microscopy both types of vacuoles could be identified as lysosomes. This abnormality of the lysosomal compartment in Tangier MNPs was not observed in Tangier fibroblasts, where the few lysosomes detected were found to be similar to those of controls. Morphological analysis of the Golgi apparatus in Tangier MNPs revealed numerous dilated Golgi cisternae, which were distributed more widely throughout the cell. However, both Tangier MNPs and especially Tangier fibroblasts showed a marked hyperplasia of the Golgi complex. Specific staining of the Golgi apparatus with the fluorescent ceramide analogue N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminocaproylsphingosine (C6-NBD-ceramide) showed that Tangier fibroblasts incorporated significantly higher amounts of C6-NBD-ceramide than did control fibroblasts. Moreover, the Tangier fibroblasts that appear generally larger than normal fibroblasts also show significant staining along the cytoskeleton, which may indicate the association of fluorescent ceramide and sphingomyelin to cytoskeletal elements. Phospholipid synthesis and catabolism were studied in Tangier fibroblasts from five patients with the use of tritiated choline as a tracer. A significantly higher incorporation rate was measured for sphingomyelin (176 +/- 18% of control) and phosphatidylcholine (144 +/- 12% of control). A moderate increase in catabolism was found for sphingomyelin (20 +/- 8% of control) and phosphatidylcholine (11 +/- 4% of control). These data are principally in agreement with our former studies of the abnormalities of phospholipid metabolism in Tangier MNPs (G. Schmitz et al, Arteriosclerosis 1990; 10:1010-1019). It is concluded that the defect in Tangier disease that we have recently described as a "disorder of intracellular traffic" (G. Schmitz et al, Proc Natl Acad Sci U S A 1985;82:6305-6309) is also expressed in Tangier fibroblasts. Tangier disease seems to be associated with morphological abnormalities of intracellular organelles, thus strongly indicating that the translocation disorder in this disease affects the Golgi apparatus and the regular processing of lysosomes and shows abnormalities in cellular lipid metabolism.
Peritoneal macrophage cholesteryl ester content as a function of plasma cholesterol in rats.
Authors: Musanti R , Chiari A , Ghiselli G
Published: June 2011

Cholesterol accumulation in macrophages that have migrated in the subintimal space leads to foam cell formation, which is believed to be one of the initiating events in atherosclerosis. In this study we investigated the effect of cholesterol feeding on peritoneal monocyte/macrophage cholesterol content and peritoneal cavity lipoprotein composition in rats. A cholesterol (2%) and cholic acid (1%) diet caused significant hypercholesterolemia in plasma, and at the same time the cholesterol content of peritoneal monocytes/macrophages was increased. At day 7, the cellular cholesteryl ester content had risen to 30.1 micrograms/mg cellular protein from a baseline value of 9.2 micrograms/mg. The unesterified cholesterol content also increased by 56%. At this time, acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity was doubled, whereas neutral and acidic cholesteryl ester hydrolase activities were unchanged. Reversal to the regular chow diet after 7 days of the cholesterol-enriched diet normalized plasma cholesterol levels as well as peritoneal monocyte/macrophage cholesteryl ester content. ACAT activity also decreased toward normal levels. Analysis of the d less than 1.21 g/ml peritoneal lipoproteins isolated by ultracentrifugation revealed the presence, in both normal and hypercholesterolemic rats, of apolipoprotein A-I-rich lipid complexes with pre-beta mobility on agarose gel electrophoresis. The size of the peritoneal lipoproteins was smaller than that of plasmatic high density lipoproteins, and their chemical composition was also different from that of the major plasma lipoproteins. The cholesteryl ester content of peritoneal lipoproteins increased after feeding of the cholesterol-enriched diet. In conclusion, our results show that cholesterol feeding leads to rapid accumulation of cholesteryl esters in monocytes/macrophages. As soon as plasma cholesterol levels are returned to normal, cellular cholesterol content is also normalized.(ABSTRACT TRUNCATED AT 250 WORDS)
Differential accumulation of intimal monocyte-macrophages relative to lipoproteins and lipofuscin corresponds to hemodynamic forces on cardiac valves in mice.
Authors: Mehrabian M , Demer L L , Lusis A J
Published: June 2011

We have studied the distribution of monocyte-macrophages, lipids, and lipoproteins in sections of aorta and aortic valves from mice fed an atherogenic diet. By immunocytochemical analysis with Mac-1 and F4/80 antibodies, apolipoprotein B antibody, and oil red O staining, three discrete regions were identified: 1) the aortic wall of the sinus of Valsalva, which contained deposits of lipid that colocalized with lipoproteins and monocyte-macrophages; 2) the sides of the aortic valve leaflets facing the ventricle, which did not contain lipids or lipoproteins but which were lined with macrophages that colocalized with lipofuscin; and 3) the sides of the leaflets facing the aorta, which did not contain lipids, lipoproteins, monocyte-macrophages, or lipofuscin deposits. This pattern of distribution resembles the expected distribution of mechanical forces, especially those of systolic blood flow, which in the three areas are predominantly 1) low-shear disturbed flow, 2) high-shear laminar flow, and 3) low-shear laminar flow, respectively. These findings suggest that lesions in the mouse closely resemble early atherosclerotic lesions in humans and other primates with respect to monocyte-macrophage and lipoprotein accumulation. The results also strikingly demonstrate that the accumulation of monocyte-macrophages and lipoproteins can occur independently, with spatial differences corresponding to the distribution of hemodynamic forces.
Cardiovascular disease and arterial calcification in insulin-dependent diabetes mellitus: interrelations and risk factor profiles. Pittsburgh Epidemiology of Diabetes Complications Study-V.
Authors: Maser R E , Wolfson S K , Ellis D , Stein E A , Drash A L , Becker D J , Dorman J S , Orchard T J
Published: June 2011

Cardiovascular disease is a frequent complication of insulin-dependent diabetes mellitus (IDDM), but the prevalence, interrelations, and risk factors of its principal components (coronary, cerebrovascular, and lower-extremity arterial disease) and of medial arterial wall calcification are not well understood. To address these issues, data from the Epidemiology of Diabetes Complications Study (n = 657) baseline examination were examined. The term coronary heart disease (CHD) was applied to those with myocardial infarction or angina, whereas lower-extremity arterial disease (LEAD) was applied to those who had undergone amputation of a lower limb or who had an ankle to arm blood pressure ratio less than 0.8 at rest or after exercise. Calcification of the lower-extremity arteries was considered to be present if ankle pressure was more than 100 mm Hg higher than brachial pressure. Although the prevalence of CHD was low, LEAD was significantly more common in women than in men (p less than 0.01), whereas calcification was more frequent in men than in women (p less than 0.01). Ten percent of those with LEAD also had CHD, and 8% with LEAD had calcification. Modeling of potential risk factors (e.g., diabetes duration and glycosylated hemoglobin) revealed that duration, female gender, fibrinogen, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and high density lipoprotein cholesterol to apolipoprotein A-I ratio were independent predictors of LEAD, whereas for CHD only, diabetes duration and hypertension contributed to CHD. Calcification revealed a mixed pattern, with duration, hypertension, and triglyceride to apolipoprotein A-I ratio being the statistically significant associated factors. The results suggest that although LEAD, CHD, and calcification often coexist, their risk factor profiles differ.
Risk factors for early carotid atherosclerosis in middle-aged French women.
Authors: Bonithon-Kopp C , Scarabin P Y , Taquet A , Touboul P J , Malmejac A , Guize L
Published: June 2011

The prevalence of carotid atherosclerosis and of its risk factors was examined in 517 apparently healthy French women, aged 45-54 years. Early phases of carotid atherosclerosis were assessed by B-mode ultrasonography. An intimal-medial thickening was found in 30.4% of the women and atheromatous plaques in 8.7%. The prevalence rate of carotid atherosclerosis increased with age, smoking, and postmenopausal status. However, after adjustment for the effect of age, postmenopausal women did not have more atherosclerotic lesions than did premenopausal women. No significant associations were found between carotid atherosclerosis and triglyceride, apolipoprotein A-I, body mass index, blood glucose, fibrinogen, plasma viscosity, or hematocrit. The mean age-adjusted levels of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and systolic and diastolic blood pressures significantly increased with the severity of carotid atherosclerosis, whereas high density lipoprotein cholesterol significantly decreased. Multiple regression analysis showed that age, smoking, high density lipoprotein cholesterol, low density lipoprotein cholesterol (or apolipoprotein B), and systolic (or diastolic) blood pressure were significantly and independently related to the severity of carotid atherosclerosis. In conclusion, the association of early carotid lesions with major cardiovascular risk factors suggests that carotid atherosclerosis may be used as a marker of the general atherosclerotic process.
The role of insulin and body fat in associations of physical activity with lipids and lipoproteins in a biethnic population. The San Luis Valley Diabetes Study.
Authors: Mayer E J , Burchfiel C M , Eckel R H , Marshall J A , Haskell W L , Hamman R F
Published: June 2011

It has been postulated that the positive effects of physical activity on high density lipoprotein cholesterol (HDL-C) and HDL-C subfraction 2 (HDL-C2) are mediated through insulin action because increased activity lowers insulin levels and lower insulin levels are associated with higher HDL-C. These relations were evaluated in a rural population of Hispanic and non-Hispanic white (NHW) adults in Colorado. Included were 138 men and 152 women with normal glucose tolerance confirmed by World Health Organization criteria. Total physical activity was assessed by 7-day recall interviews. No significant associations were observed among women. Among men, activity was inversely associated with fasting insulin (r = -0.17, p less than 0.05). From analysis of covariance models including the interaction term activity x ethnicity, total HDL-C was 43.4 mg/dl (95% confidence interval [CI] = 39.1, 47.7) in the low tertile of activity and 50.4 mg/dl (95% CI = 46.3, 54.5) in the high tertile for NHW men, after adjustment for fasting insulin, fasting glucose, body mass index (BMI), waist to hip ratio (WHR), and age. For Hispanic men, adjusted HDL-C was 43.4 mg/dl (95% CI = 38.6, 48.2) and 49.1 mg/dl (95% CI = 44.0, 54.2) in the low and high tertiles, respectively. Adjusted HDL-C2 levels were 52% higher in the most compared with the least active NHW men, whereas there was no difference by activity for Hispanic men. Higher adjusted mean levels of HDL-C3 were observed for the high compared with the low activity tertile in both ethnic groups. Ethnicity-specific models showed that for NHW men, activity explained 12% (p = 0.01), fasting insulin explained 5% (p = 0.05), and BMI explained 6% (p = 0.04) of the variability in total HDL-C, after adjustment for fasting glucose, WHR, and age. These models confirmed that effects of insulin and body fat did not explain the observed associations between activity and total HDL-C and its subfractions.
Sluggish sitosterol turnover and hepatic failure to excrete sitosterol into bile cause expansion of body pool of sitosterol in patients with sitosterolemia and xanthomatosis.
Authors: Bhattacharyya A K , Connor W E , Lin D S , McMurry M M , Shulman R S
Published: June 2011

Sitosterolemia and xanthomatosis are characterized by the development of tendon and tuberous xanthomas at an early age and premature atherosclerosis despite normal plasma cholesterol concentrations. The reason(s) for the xanthoma formation and premature atherosclerosis are not clearly understood. The accumulation of sitosterol in the tissues of these patients could be due to increased uptake of low density lipoprotein (LDL) via LDL receptors because of an expanded sitosterol pool caused by sluggish turnover and decreased excretion of sitosterol into bile and feces coupled with the hyperabsorption of sitosterol. We have studied sitosterol and cholesterol turnovers, the biliary and fecal excretion of neutral and acidic steroids, and the response of plasma sterol (sitosterol and cholesterol) levels to either a sterol-free formula or low plant sterol diet in three patients. The average half-life of the first exponential (tA1/2) for sitosterol was 9.2 +/- 3.3 (mean +/- SD) days, which was more than twice that in normal humans. The second exponential (tB1/2) was 156 +/- 108 days, which was nearly 10 times longer than that for normal humans. The average cholesterol production rate in pool A was 0.87 g/day, which is about 40% of that in normal humans. Cholesterol synthesis measured by the sterol balance technique was also found to be about 70% lower than that for normal humans. In two patients fed a sterol-free formula diet, by 25 days their plasma sitosterol and cholesterol levels had decreased by 42% and 36%, respectively. However, in one patient plasma sitosterol and cholesterol concentrations remained unchanged while on the low plant sterol-mixed food diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Dynamics of shear-induced redistribution of F-actin in endothelial cells in vivo.
Authors: Langille B L , Graham J J , Kim D , Gotlieb A I
Published: June 2011

The steady-state responses of endothelial cell F-actin distribution to changes in in vivo shear stress have been well documented. The purpose of the current work was to define the dynamics of redistribution of F-actin in the period immediately after experimental changes in shear. We used abdominal aortic coarctation in rabbits to experimentally increase shear stress downstream from the coarctation by approximately twofold. In situ staining was employed to track subsequent F-actin redistribution. Within 12-15 hours, the number of stress fibers in the central regions of the cells decreased, and some separation of junctional actin in adjacent cells occurred. Long, central stress fibers of variable thickness were evident at 24 hours, but the band of actin normally seen at the periphery of the cells could no longer be distinguished. The redistribution of F-actin was completed over the next 24 hours by an increase in thickness of central stress fibers. Restoration of normal F-actin distribution after coarctations were removed proceeded more slowly. The long, thick stress fibers that were induced by high shear were replaced by thinner or shorter microfilament bundles 48 hours after the coarctations were removed. At 72 hours, central stress fibers were primarily long, thin structures. Peripheral F-actin was not fully restored at this time. Peripheral F-actin was restored at 1 week after removal of the coarctation, but there were still more and longer stress fibers at this time than were observed in control aortas.(ABSTRACT TRUNCATED AT 250 WORDS)
Monocytes may amplify their recruitment into inflammatory lesions by inducing monocyte chemotactic protein.
Authors: Cushing S D , Fogelman A M
Published: June 2011

By Northern analysis, freshly isolated monocytes contained no detectable mRNA for monocyte chemotactic protein-1 (MCP-1). However, after 4 hours of incubation at 37 degrees C, MCP-1 mRNA was clearly induced in the monocytes and was found to be highly dependent and directly proportional to the monocyte density. The level of MCP-1 mRNA continued to increase, reaching a peak after 22 hours of incubation. After 3 days in culture, MCP-1 mRNA levels had declined substantially and after 8 days were undetectable in the monocytes/macrophages. The amount of MCP-1 protein secreted correlated with the density-dependent increase in MCP-1 message. We hypothesize that the migration of monocytes into inflammatory lesions may be amplified by the density and time-dependent induction of MCP-1.
Demonstration of a keratan sulfate-containing proteoglycan in atherosclerotic aorta.
Authors: Robbins R A , Wagner W D , Register T C , Caterson B
Published: June 2011

Proteoglycans were isolated from either grossly normal or atherosclerotic pigeon aortas after extraction with 4 M guanidine hydrochloride and purification by ion-exchange and size-exclusion chromatography. The small-size proteoglycans (Kav 0.4, on Sepharose CL-4B) from both normal and atherosclerotic tissue contained primarily a dermatan sulfate proteoglycan with an intact molecular size of 220-330 kd and a 45-kd core protein. In addition to the dermatan sulfate proteoglycan, the preparation contained a proteoglycan recognized by monoclonal antibody (MAb) 5-D-4, indicating the presence of sulfated poly-N-acetyllactosamine sequences common to corneal and cartilage keratan sulfate. Electrophoresis on sodium dodecyl sulfate-polyacrylamide gel revealed a polydisperse proteoglycan of 60-150 kd that was recognized by MAb 5-D-4. Significantly greater immunoreactivity with MAb 5-D-4 was observed for atherosclerotic compared with normal artery. After endo-beta-D-galactosidase treatment of the proteoglycan from atherosclerotic aorta, diminished MAb 5-D-4 reactivity observed by both Western blot analysis and enzyme-linked immunosorbent assay demonstrated that the material was keratan sulfate. Endo-beta-D-galactosidase treatment of the intact proteoglycan generated core proteins of 28 and 38 kd. These studies suggest the presence of one or more keratan sulfate proteoglycans in grossly normal and atherosclerotic arteries. Immunochemical data suggest that sulfation of the keratan sulfate proteoglycan may be greater in atherosclerotic aorta.
Beta-VLDL-induced cholesterol ester deposition in macrophages may be regulated by neutral cholesterol esterase activity.
Authors: Ishii I , Oka M , Katto N , Shirai K , Saito Y , Hirose S
Published: June 2011

We examined the role of enzyme activities involved in cholesterol ester metabolism in the accumulation of cholesterol ester in macrophages. When [3H]cholesterol linoleate-beta-very low density lipoproteins (beta-VLDLs) were incubated with rat resident peritoneal macrophages (RPMs), thioglycolate-elicited macrophages (TEMs), or alveolar macrophages (AMs), cholesterol ester accumulation was the greatest in TEMs and the least in AMs. The uptake of [3H]cholesterol linoleate-beta-VLDL into AMs was four times that into RPMs, and the uptake into TEMs was twice that into RPMs. The [3H]cholesterol released from [3H]cholesterol linoleate-beta-VLDL-loaded AMs was five times higher than from TEMs and RPMs, whereas those from RPMs and TEMs were almost the same. In studies using cell homogenates, the acid cholesterol esterase activity in AMs was 1.7 times that in TEMs and six times that in RPMs. The acyl-coenzyme A:cholesterol acyltransferase (ACAT) activities in AMs and TEMs were similar but were higher than that in RPMs. The neutral cholesterol esterase activity was seven times higher in AMs than in RPMs and TEMs. In the study using intact cells, the hydrolysis of loaded [3H]cholesterol linoleate-beta-VLDL in the presence of the ACAT inhibitor CL277,082 and the cholesterol [14C]oleate synthesis from [14C]oleate were enhanced in AMs about twofold compared with RPMs and TEMs. The reduction of de novo synthesized cholesterol [14C]oleate in the presence of CL277,082 was enhanced in AMs four times compared with TEMs or RPMs.(ABSTRACT TRUNCATED AT 250 WORDS)
Reevaluation of regression of coronary arteriosclerotic lesions in repeat-spawning steelhead trout.
Authors: Farrell A P , Johansen J A
Published: June 2011

At spawning, migratory salmonids have an extensive accumulation of coronary arteriosclerotic lesions. Nevertheless, when steelhead trout (Oncorhynchus mykiss) return to the ocean after spawning, an unusual phenomenon has been reported, namely, that these lesions have regressed naturally and almost completely (R.L. Van Citters and N.W. Watson, Science 1968; 159:105-107). In contrast to this earlier finding, we present data that show a high prevalence and severity of coronary lesions in 1) wild, repeat-spawning steelhead trout that were caught at high sea and 2) wild and cultured steelhead trout that had been held in sea pens for up to 1 year after maturation. Therefore, we refute the idea of natural lesion regression in steelhead trout. Coronary lesions in salmonids are characteristically lipid free despite the fact that there are high plasma levels of both total cholesterol and low density lipoproteins. This situation contrasts with the characteristic lipid deposition during lesion development in mammals. We therefore suggest that attention should be directed to explaining why coronary lesions accumulate despite very high dietary levels of omega-3 polyunsaturated fatty acids in the diets and tissues of these fish.
Apo(a) isoforms predict risk for coronary heart disease. A study in six populations.
Authors: Sandholzer C , Saha N , Kark J D , Rees A , Jaross W , Dieplinger H , Hoppichler F , Boerwinkle E , Utermann G
Published: June 2011

Elevated concentrations of lipoprotein(a) (Lp[a]) in plasma are associated with premature coronary heart disease (CHD). Lp(a) levels are largely determined by alleles at the hypervariable apolipoprotein(a) (apo[a]) gene locus, but other genetic and environmental factors as well as diseases also affect plasma Lp(a) concentrations. It is therefore unclear whether Lp(a) is a primary genetic risk factor or whether Lp(a) levels are elevated secondary to disease in CHD patients. We have analyzed apo(a) phenotypes that represent a stable genetic trait in subjects with CHD and control subjects from different populations representing a variety of ethnic groups (Tyrol, Germany, Wales, Israel, Singapore Chinese, and Singapore Indian). Despite differences in sampling design and disease definition in this multipopulation case-control study, those apo(a) isoforms associated with high Lp(a) plasma concentrations (B, S1, and S2) were more frequent in the CHD patients in each ethnic group. These differences were significant in three of the studied populations and highly significant (p < 0.001) in the pooled (total) group. Lp(a) concentrations were also measured in all groups except Germans and were found to be consistently higher in cases than in control subjects in each ethnic group. For all but one population (Israeli) the differences were significant. The effects of the apo(a) size polymorphism on Lp(a) levels were similar in CHD patients and control subjects from different populations. The data demonstrate that alleles at the apo(a) locus determine the risk for CHD through their effects on Lp(a) concentrations across multiple populations with large differences in CHD frequency and risk factor profiles.
Hepatic ACAT activity in African green monkeys is highly correlated to plasma LDL cholesteryl ester enrichment and coronary artery atherosclerosis.
Authors: Carr T P , Parks J S , Rudel L L
Published: June 2011

Previous studies and this study of African green monkeys show a strong positive correlation between plasma low density lipoprotein (LDL) size and the extent of coronary artery atherosclerosis (CAA). Increased LDL size was principally due to the accumulation of cholesteryl oleate molecules within the particle core, suggesting that many of these cholesteryl esters were of tissue origin, i.e., from the acyl-coenzyme A:cholesterol acyltransferase (ACAT) reaction instead of the lecithin:cholesterol acyl-transferase (LCAT) reaction. The current study was conducted to test the hypothesis that ACAT in the liver is the source of the increased numbers of cholesteryl oleate molecules in plasma LDL particles that appear to increase the atherogenic potential of LDL. Monkeys were fed diets rich in fat (lard, safflower oil, or fish oil) and cholesterol for 3-6 years before liver perfusion, ACAT assay, and evaluation of CAA. Hepatic ACAT activity was positively correlated with hepatic cholesteryl ester secretion (r = 0.61, p < 0.001), plasma LDL cholesteryl ester content (r = 0.60, p < 0.0001), and the extent of CAA (r = 0.62, p < 0.0001). The number of cholesteryl oleate molecules within LDL increased proportionally with LDL size in each of the diet groups. Hepatic cholesteryl oleate concentration was correlated with the accumulation of cholesteryl oleate in liver perfusate (r = 0.72, p < 0.01) and with plasma LDL cholesterol oleate content (r = 0.73, p < 0.0001). Our interpretation is that these data, obtained in a relevant primate model of CAA, suggest that hepatic ACAT increases the atherogenicity of LDL by augmenting both the secretion by the liver and accumulation in plasma LDL of cholesteryl oleate.
Effect of endothelial integrity, transmural pressure, and time on the intimal-medial uptake of serum 125I-albumin and 125I-LDL in an in vitro porcine arterial organ-support system.
Authors: Fry D L , Haupt M W , Pap J M
Published: June 2011

This report describes a new in vitro, metabolically supported, Sinclair Research Farm minipig aortic preparation in which the intimal-medial uptakes (M, mg.cm-2 of intimal surface) of porcine 125I-albumin and normocholesterolemic (nonoxidized) porcine 125I-low density lipoprotein (LDL) from a stirred, autogenous serum (containing a 125I-protein concentration of c0, mg.cm-3 at 37 degrees C and pH 7.4) were studied as functions of transmural pressure (0 < or = P < or = 150 mm Hg), time (30 < or = t < or = 120 minutes), and endothelial integrity. The following new observations were made: 1) The normalized transendothelial uptakes (M/c0, cm) of both albumin and LDL across normal intact aortic endothelial surfaces were insensitive to P. This indicated that these macromolecular solutes were not readily convected across the normal aortic endothelial surface despite increasing P. 2) However, the associated transendothelial M/c0 versus t relations for the normal intact surfaces were shown to increase monotonically with t in a manner consistent with a simple diffusive transport across a large surface barrier into the subjacent media, either with (Cases 2A and 2B) or without (Case 1) an associated transmural water convection. 3) The shapes of these temporal M/c0 curves of albumin and LDL were virtually the same; however, the magnitude of the albumin M/c0 curve was about sevenfold greater than that of LDL. 4) The M/c0 across the injured endothelial surface (Case 2C) not only increased monotonically with t but also increased significantly with P, indicating that in the absence of a normal endothelial surface, a very large convective component was added to the transport processes across the exposed aortic endothelial basement membrane and internal elastica. We conclude that: 1) the normal porcine aortic endothelial surface can provide a virtually complete barrier to the transendothelial convective transport of both albumin and LDL, 2) the diffusive barrier of the normal endothelial surface to LDL was sevenfold greater than that to albumin, 3) loss of the endothelial cell layer was associated with a threefold increase in the (P = 0) diffusive intimal-medial uptake of serum albumin in contrast to an eightfold increase in the pressurized (P = 150 mm Hg) combined diffusive-convective intimal-medial albumin uptake in the same vessel.
Mast cell-mediated inhibition of reverse cholesterol transport.
Authors: Lee M , Lindstedt L K , Kovanen P T
Published: June 2011

Net cholesterol efflux from cholesterol-loaded macrophages, i.e., foam cells, was induced by incubating the foam cells with high density lipoprotein3 (HDL3). However, when the incubation system included rat serosal mast cells stimulated to trigger exocytosis of their cytoplasmic secretory granules, the ability of HDL3 to induce cholesterol efflux was largely lost. This loss was found to be due to the proteolytic action of chymase, the neutral protease of the granules, which degraded the apolipoproteins of HDL3, so rendering them unable to mediate cholesterol efflux from the foam cells. The observation defines a novel cell-dependent mechanism that blocks the initial steps of reverse cholesterol transport and suggests a role for mast cell chymase in cellular accumulation of cholesterol, an early stage in atherogenesis.
Regulation of lipoprotein lipase secretion in murine macrophages during foam cell formation in vitro. Effect of triglyceride-rich lipoproteins.
Authors: Sofer O , Fainaru M , Schafer Z , Goldman R
Published: June 2011

Triglyceride rich-lipoproteins induce triglyceride accumulation in macrophages, leading to foam cell formation. The correlation between cell triglyceride accumulation and lipoprotein lipase (LPL) secretion in murine macrophages and the role that LPL plays in the accumulation process were examined. LPL secretion is defined as the extracellular LPL activity that accumulates during a 4-hour incubation of treated and untreated cells in a bovine serum albumin-containing RPMI-1640 medium. LPL secretion was suppressed (up to 70%) in a dose- and time-dependent manner when J774.1 cells were incubated with chylomicrons, very low density lipoproteins, and intermediate density lipoproteins but not with low or high density lipoproteins from normolipidemic and hypertriglyceridemic subjects. Oleic acid both suppressed LPL secretion and invoked triglyceride accumulation. Suppression of LPL secretion preceded gross triglyceride accumulation, was reversible, and was not the result of a reduction in LPL mRNA. P388D1 cells neither secreted LPL nor accumulated triglyceride. Inhibition of LPL secretion by tunicamycin in both peritoneal macrophages and J774.1 cells prevented a hypertriglyceridemic very low density lipoprotein-induced triglyceride accumulation, an effect that was counteracted by addition of exogenous LPL. The results suggest that 1) extracellular hydrolysis of lipoprotein triglyceride is a major factor in inducing foam cell formation and 2) LPL secretion may be regulated by cell energy needs, and when these needs are exceeded, LPL secretion is suppressed.
Increased lipid binding to thrombi in coronary artery disease. Findings in patients without premedication in native (not anticoagulated) test systems.
Authors: Kunz F , Pechlaner C , Erhart R , Zwierzina W D , Kemmler G
Published: June 2011

Thrombi and clots were produced from native (i.e., not anticoagulated) platelet-rich and platelet-poor plasma from patients with coronary artery disease and control subjects who had not taken any medication known to influence plasma lipids, coagulation, or platelet aggregation. The clotting times were recorded, and the lipid content of clots, thrombi, platelets, plasma, and high density lipoprotein was analyzed. Thrombi produced from native platelet-rich plasma were 46% heavier in coronary artery disease patients and contained about 20% more phospholipids and free cholesterol and about twice the amount of triglycerides and esterified cholesterol in both absolute and relative amounts with respect to the corresponding lipids of plasma plus platelets. The elevated content of lipids not only increases the size of the thrombi but also changes their quality because of an increased content in plasmatic lipids, as platelets contain only trace amounts of triglycerides and cholesterol esters. In agreement herewith, fibrinogen and maximal amplitude on the thrombelastogram were increased in coronary artery disease patients, whereas the thrombus-forming time and clotting times of platelet-poor and platelet-rich plasma were shortened, indicating accelerated coagulation and activation of platelets. Analysis of these results suggests a disturbed interrelation in coronary artery disease between lipids and hemostasis, in which platelets, high density lipoprotein, and lipoproteins rich in triglycerides and cholesterol esters may play a role.
Oxidation of low density lipoprotein enhances its potential to increase intracellular free calcium concentration in vascular smooth muscle cells.
Authors: Weisser B , Locher R , Mengden T , Vetter W
Published: June 2011

There have been suggestions that oxidation of low density lipoproteins (LDL) might increase their atherogenic potential. Because changes in intracellular free calcium concentration [Ca2+]i have been linked to atherogenesis, we compared the influence of oxidized LDL (Ox-LDL) and native LDL (N-LDL) on [Ca2+]i in vascular smooth muscle cells cultured from rat aortas. For determination of [Ca2+]i, fura-2 fluorescence was used. LDL was isolated by ultracentrifugation from the sera of human donors (n = 17). In N-LDL, oxidation was prevented by addition of antioxidants, whereas Ox-LDL was obtained by auto-oxidation. The extent of oxidation was assessed by measurement of thiobarbituric acid-reactive substances. Addition of Ox-LDL (20 micrograms protein/ml) to the vascular smooth muscle cells induced a mean increase of 129 +/- 13% in [Ca2+]i compared with 81 +/- 7% with N-LDL (p less than 0.01). Dose-response curves from 1 to 20 micrograms/ml (six experiments) confirmed this difference within the entire dose range. These results indicate that a more pronounced increase in [Ca2+]i induced by Ox-LDL might be one of the cellular mechanisms responsible for the higher atherogenic potential of Ox-LDL compared with N-LDL, as [Ca2+]i is an important second-messenger system involved in many atherogenic processes such as hypertrophy, cell migration, and cell damage.
Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat.
Authors: Staels B , van Tol A , Andreu T , Auwerx J
Published: June 2011

The influence of different fibrates on apolipoprotein metabolism was investigated. Administration of fenofibrate provoked a dose-dependent decrease in plasma cholesterol concentration that was already evident after 1 day. Intestinal apolipoprotein (apo) A-I and apo A-IV mRNA levels remained fairly constant. In contrast, liver apo A-I, apo A-II, and apo A-IV mRNA levels decreased in a dose-dependent fashion, which was associated with a lower transcription rate of the apo A-I but not the apo A-II gene. The decline in hepatic apo A-I, apo A-II, and apo A-IV mRNA had already started after 1 day and was associated with a drop in plasma apo A-I and apo A-IV concentrations. Plasma apo E had already decreased after 1 day of fenofibrate, whereas apo B initially remained constant and increased only after 14 days of fenofibrate at the highest dose. Hepatic and intestinal apo B mRNA contents and liver, heart, kidney, and testis apo E mRNA contents were only marginally affected after treatment with fenofibrate. Liver low density lipoprotein receptor mRNA levels rose slightly after a 3-day administration of the highest dose of fenofibrate. Both clofibrate and gemfibrozil had effects comparable to those of fenofibrate on liver and intestinal apolipoprotein mRNA levels except for liver apo A-II mRNA, which decreased only marginally. Compared with fenofibrate, clofibrate caused similar changes in plasma cholesterol, apo A-I, apo A-IV, and apo E concentrations, whereas gemfibrozil increased plasma cholesterol and apo E without changing apo A-I and apo A-IV concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Structural changes and recovery of function after arterial injury.
Authors: Jamal A , Bendeck M , Langille B L
Published: June 2011

Repair and remodeling processes initiated by arterial injury are thought to be critical in the pathogenesis of important vascular disorders. However, how these processes are related to specific types of injury is not well defined. Consequently, we compared arterial responses to several types of injury. Segments of rabbit carotid arteries were injured by intraluminal passage of an inflated embolectomy catheter, by hyperdistending the arteries with sterile saline, or by flushing them briefly with Triton X-100. Ballooning and Triton treatment removed the endothelium while imposing hyperdistending or nonhyperdistending injury on the vessel media. Hyperdistension with sterile saline caused medial injury but only transient and focal endothelial denudation. All modes of injury caused medial damage that was repaired within 2-7 days as assessed by vessel wall DNA content and synthesis and by capacity to contract. In addition, ballooned arteries recovered their capacity to exhibit diameter reductions induced by decreased blood flow once the endothelium had regenerated. The two injuries that caused endothelial denudation, ballooning and Triton treatment, resulted in equal intimal thickening after 6 weeks despite lower short- and long-term rates of cell replication after Triton-induced injury. Only ballooning resulted in chronic turnover of intimal smooth muscle cells after injury. No neointimal proliferation followed hyperdistension with saline despite significant medial injury. These latter findings suggest that even severe medial injury does not lead to intimal proliferation in the absence of endothelial denudation.