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S Fazio

Publications and source records attributed to S Fazio.

At least 37 records · Page 2Linked to original sources
PubMed2000

The cell biology and physiologic relevance of ApoE recycling.

Apolipoprotein E (apoE) is unique among the different apoproteins because of its many functions in the assembly, processing, and removal of plasma lipoproteins. Some of these functions require the presence of apoE inside the cell or in close association with its outer membrane. For example, the presence of apoE increases triglyceride content in newly formed very low-density lipoprotein (VLDL), whereas the fast removal of chylomicrons requires the presence of a cellular pool of apoE ready to surface and bind to membrane proteoglycans and possibly to lipoprotein receptors such as the LDL receptor-related protein (LRP). Our recent discovery that VLDL-apoE internalized by hepatocytes is partially protected from lysosomal degradation and recycles through the Golgi apparatus suggests that the biologic cycle of apoE may not be concluded when the lipoprotein is taken up by the cell, and that recycling apoE may have a physiologic role in lipoprotein assembly, remnant removal, and cholesterol efflux.

Animals↗
PubMed2000

Establishing the efficacy and cost effectiveness of community intensive case management of long-term mentally ill: a matched control group study.

OBJECTIVE: The study attempted to identify whether chronic mentally ill persons after receiving intensive case management (ICM) could demonstrate improved inpatient service utilisation compared with a matched control group cohort. Costings were measured to observe whether the increase in providing intensive outpatient contacts would be offset by savings in reduced inpatient service utilisation. METHOD: Eighty ICM patients were matched on ICD-9 diagnosis, age, gender, length of illness, age at first inpatient and outpatient contact, marital status, educational level, employment status, country of birth, year of arrival to Australia and religion. Inpatient bed-days and outpatient contacts were recorded and compared 12 months prior to ICM treatment, 12 and 24 months after ICM using within/between group repeated measures analysis of variance. RESULTS: The ICM group demonstrate significant reductions in inpatient service utilisation both within the 12- and 24-month period after receiving ICM treatment. The cost differential by 24 months of treatment was $801,475 in favour of the ICM model. The increase in costs of outpatient contacts were offset by a significant reduction in inpatient service utilisation. CONCLUSION: When outpatient contacts averaged one contact a week for the duration of the study period no significant reductions in inpatient service utilisation was recorded, as demonstrated by comparison with the matched control group. By increasing outpatient contacts by 3-4 contacts a week, inpatient contacts reduced by 36.8%. ICM is an efficacious and cost effective way to implement community-based services to the chronically long-term mentally ill.

Adult↗
PubMed2000

Reduced atherosclerotic lesions in mice deficient for total or macrophage-specific expression of scavenger receptor-A.

The absence of the scavenger receptor A (SR-A)-I/II has produced variable effects on atherosclerosis in different murine models. Therefore, we examined whether SR-AI/II deficiency affected atherogenesis in C57BL/6 mice, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, and whether the deletion of macrophage SR-AI/II expression would modulate lesion growth in C57BL/6 mice and LDL receptor (LDLR)(-/-) mice. SR-AI/II-deficient (SR-AI/II(-/-)) female and male mice on the C57BL/6 background were challenged with a butterfat diet for 30 weeks. No differences were detected in plasma lipids between SR-AI/II(-/-) and SR-AI/II(+/+) mice, whereas both female and male SR-AI/II(-/-) mice had a tremendous reduction (81% to 86%) in lesion area of the proximal aorta compared with SR-AI/II(+/+) mice. Next, to analyze the effect of macrophage-specific SR-AI/II deficiency in atherogenesis, female C57BL/6 mice were lethally irradiated, transplanted with SR-AI/II(-/-) or SR-AI/II(+/+) fetal liver cells, and challenged with the butterfat diet for 16 weeks. In a separate experiment, male LDLR(-/-) mice were reconstituted with SR-AI/II(-/-) or SR-AI/II(+/+) fetal liver cells and challenged with a Western diet for 10 weeks. No significant differences in plasma lipids and lipoprotein profiles were noted between the control and experimental groups in either experiment. SR-AI/II(-/-)-->C57BL/6 mice, however, had a 60% reduction in lesion area of the proximal aorta compared with SR-AI/II(+/+)-->C57BL/6 mice. A similar level of reduction (60%) in lesion area was noted in the proximal aorta and the entire aorta en face of SR-AI/II(-/-)-->LDLR(-/-) mice compared with SR-AI/II(+/+)-->LDLR(-/-) mice. These results demonstrate in vivo that SR-AI/II expression has no impact on plasma lipid levels and that macrophage SR-AI/II contributes significantly to atherosclerotic lesion formation.

Animals↗
PubMed2000

Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1.

Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) have attracted considerable interest as a potential treatment for atherosclerosis. Currently available inhibitors probably act nonselectively against the two known ACATs. One of these enzymes, ACAT1, is highly expressed in macrophages in atherosclerotic lesions, where it contributes to foam-cell formation. In this study, we examined the effects of selective ACAT1 deficiency in two mouse models of atherosclerosis. In the setting of severe hypercholesterolemia caused by deficiency in apoE or the LDL receptor (LDLR), total ACAT1 deficiency led to marked alterations in cholesterol homeostasis and extensive deposition of unesterified cholesterol in the skin and brain. Bone marrow transplantation experiments demonstrated that ACAT1 deficiency in macrophages was sufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice. ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relatively lower serum cholesterol levels. However, the lesions in ACAT1-deficient mice were atypical in composition, with reduced amounts of neutral lipids and a paucity of macrophages in advanced lesions. Although the latter findings may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in the setting of severe hyperlipidemia may have detrimental consequences.

Animals↗
PubMed2000

Cardiovascular effects of short-term growth hormone hypersecretion.

Many studies have shown that acromegaly has relevant effects on cardiovascular system, but few data are available regarding the effects of short-term acromegaly on heart morphology and function. These data would help to clarify the natural history of acromegalic disease and could provide new insight into the mechanisms of GH action on the human heart. Therefore, we studied by Doppler echocardiography a group of 10 young subjects strictly selected as having short-term (<5 yr) uncomplicated acromegaly. The results of this study have shown that shortterm acromegaly is characterized by significantly increased left ventricular mass (P<0.005), with normal relative wall thickness, associated with Doppler indices of diastolic function in the normal range. Furthermore, stroke index and cardiac index were significantly enhanced in the patient group (P<0.01 and P<0.001, respectively), whereas systemic vascular resistance was significantly reduced (P<0.001). In conclusion, our study shows that short-term acromegaly significantly affects the heart, but, at variance with long-term disease, it is characterized by increased left ventricular mass, with eccentric remodeling and normal diastolic function. Moreover, short-term acromegaly induces a high cardiac output state with reduction of systemic vascular resistance.

Acromegaly↗
PubMed2000

Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients.

To determine the clinical impact of endogenous subclinical hyperthyroidism, specific symptoms and signs of thyroid hormone excess and quality of life were assessed in 23 patients (3 males and 20 females; mean age, 43 +/- 9 yr) and 23 age-, sex-, and lifestyle-matched normal subjects by using the Symptoms Rating Scale and the Short Form 36 Health Survey questionnaires. Because the heart is one of the main target organs of the thyroid hormone, cardiac morphology and function were also investigated by means of standard 12-lead electrocardiogram (ECG), 24-h Holter ECG, and complete Doppler echocardiography. Stable endogenous subclinical hyperthyroidism had been diagnosed in all patients at least 6 months before the study (TSH, 0.15 +/- 0.1 mU/L; free T(3), 6.9 +/- 1.1, pmol/L; free T(4), 17.2 +/- 2.3, pmol/L). Fifteen patients were affected by multinodular goiter, and eight patients by autonomously functioning thyroid nodule. The mean Symptoms Rating Scale score (9. 8 +/- 5.5 vs. 4.3 +/- 2.2, P: < 0.001) and both the mental (36.1 +/- 9.5 vs. 50.0 +/- 8.5, P: < 0.001) and physical (42.6 +/- 8.0 vs. 55. 6 +/- 4.1, P: < 0.001) component scores of Short Form 36 Health Survey documented a significant prevalence of specific symptoms and signs of thyroid hormone excess and notable impairment of quality of life in patients. Holter ECG showed a higher prevalence of atrial premature beats in endogenous subclinical hyperthyroid patients than in the controls, but the difference was not statistically significant, although the average heart rate was significantly increased in the patients (P: < 0.001). An increase of left ventricular mass (162 +/- 24 vs. 132 +/- 22 g, P: < 0.001) due to the increase of septal (P: = 0.025) and posterior wall (P: = 0.004) thickness was observed in patients. Systolic function was enhanced in patients as shown by the significant increase of both fractional shortening (P: = 0.005) and mean velocity of heart rate-adjusted circumferential fiber shortening (P: = 0.036). The Doppler parameters of diastolic function were significantly impaired in the patients as documented by the reduced early to late ratio of the transmitral flow velocities (P: < 0.001) and the prolonged isovolumic relaxation time (P: = 0.006). These data indicate that endogenous subclinical hyperthyroidism has a relevant clinical impact and that it affects cardiac morphology and function. Moreover, they suggest that treatment of persistent endogenous subclinical hyperthyroidism should be considered also in young and middle-aged patients to attenuate specific symptoms and signs of thyroid hormone excess, ameliorate the quality of life, and avoid the consequences to the heart of long exposure to a mild excess of thyroid hormone.

Adult↗
PubMed2000

Myocardial ischemia caused by an hydatid cyst of the interventricular septum successfully treated with albendazole.

We report the case of a 33-year-old patient with clinical history of echinococcosis admitted to our Hospital for the appearance of chest pain and electrocardiographic findings of anterior ischemia. The cardiac enzymogram was in the normal range, the chest roentgengram did not show any pathological findings, but two-dimensional echocardiography revealed the presence of a small circular area in the interventricular septum. Transesophageal echocardiography and cardiac nuclear magnetic resonance confirmed the presence of a small hydatid cyst in the middle ventricular septum; in addition, a myocardial scintigraphy revealed an apical stress defect with late reperfusion. Besides cardiologic therapy, the patient was treated with albendazole, an antiparasitic drug, 400 mg bid, for cycles of 28 days with 14 day withdrawal. After two cycles of albendazole therapy, two-dimensional echocardiography showed the absence of the round cystic mass of the interventricular septum previously described. In conclusion, in the case described, long-term therapy with albendazole determined the complete recovery from the illness with the simultaneous disappearance of the cyst and of clinical and electrocardiographic findings of myocardial ischemia.

Adult↗
PubMed2000

[Myocardial metabolism of calcium in heart failure: from physiology to new therapeutic perspectives].

Development of heart failure is associated with an impairment of intracellular calcium handling. The precise mechanisms involved are still obscure. When membrane depolarization occurs, a small amount of extracellular calcium enters the intracellular milieu through the L-type channels. Such "trigger" calcium acts on specific receptors of the sarcoplasmic reticulum, that, in turn, according to the so-called calcium entry-calcium release mechanism, allows the release of a larger amount of calcium from the sarcoplasmic reticulum. Removal of calcium from the cytosol is the key event of the diastolic phase. Calcium removal from cytosol occurs through specific membrane pumps. Recent therapeutic approaches involving gene targeting of calcium pumps have yielded promising results. Specifically, increased levels of SERCA 2 in the myocardium have shown to enhance cardiac contractility under normal circumstances and in experimental heart failure. Future research is needed to confirm these findings in human heart failure.

Calcium↗
PubMed1999

A direct role for the macrophage low density lipoprotein receptor in atherosclerotic lesion formation.

To evaluate the contribution of the macrophage low density lipoprotein receptor (LDLR) to atherosclerotic lesion formation, we performed bone marrow transplantation studies in different mouse strains. First, LDLR(-/-) mice were transplanted with either LDLR(+/+) marrow or LDLR(-/-) marrow and were challenged with an atherogenic Western type diet. The diet caused severe hypercholesterolemia of a similar degree in the two groups, and no differences in the aortic lesion area were detected. Thus, macrophage LDLR expression does not influence foam cell lesion formation in the setting of extreme LDL accumulation. To determine whether macrophage LDLR expression affects foam cell formation under conditions of moderate, non-LDL hyperlipidemia, we transplanted C57BL/6 mice with either LDLR(-/-) marrow (experimental group) or LDLR(+/+) marrow (controls). Cholesterol levels were not significantly different between the two groups at baseline or after 6 weeks on a butterfat diet, but were 40% higher in the experimental mice after 13 weeks, mostly due to accumulation of beta-very low density lipoprotein (beta-VLDL). Despite the increase in cholesterol levels, mice receiving LDLR(-/-) marrow developed 63% smaller lesions than controls, demonstrating that macrophage LDLR affects the rate of foam cell formation when the atherogenic stimulus is beta-VLDL. We conclude that the macrophage LDLR is responsible for a significant portion of lipid accumulation in foam cells under conditions of dietary stress.

Animals↗
PubMed1999

Retroviral gene therapy in ApoE-deficient mice: ApoE expression in the artery wall reduces early foam cell lesion formation.

BACKGROUND: Apolipoprotein E (apoE) has long been known to play an important role in the clearance of plasma lipoproteins. More recently, a direct role for apoE in delaying atherogenesis has been proposed. Macrophage production of apoE in the artery wall has been demonstrated to provide protection against atherosclerotic lesion development independently from its role in lipoprotein clearance. However, whether macrophage apoE can affect lesion growth at all stages of atherogenesis remains to be established. METHODS AND RESULTS: To evaluate the role of macrophage apoE in different stages of atherogenesis, as well as to establish a novel gene therapy approach to atherosclerotic vascular disease, we used an apoE-expressing retrovirus to transduce apoE-deficient (-/-) bone marrow for transplantation into apoE(-/-) recipient mice. Three weeks after bone marrow transplantation, apoE was expressed from arterial macrophages and was detectable in plasma associated with lipoproteins at 0.5% to 1% of normal levels but did not affect plasma cholesterol levels. We used 2 groups of recipient mice: younger mice with lesions consisting primarily of foam cells and older mice with more advanced lesions. When either the mouse or human apoE transgenes were expressed in mice from 5 to 13 weeks of age, there was a significant reduction in lesion area, whereas no effects were detected in mice that expressed apoE from 10 to 26 weeks of age. CONCLUSIONS: We demonstrate that arterial macrophage apoE secretion can delay atherogenesis if expressed during foam cell formation but is not beneficial during the later stages of atherogenesis. These data also provide evidence that apoE transgene expression from arterial macrophages may have therapeutic applications.

Animals↗
PubMed1999

Recycling of apolipoprotein E in mouse liver.

Following the internalization of low density lipoprotein (LDL) by the LDL receptor within cells, both the lipid and the protein components of LDL are completely degraded within the lysosomes. Remnant lipoproteins are also internalized by cells via the LDL receptor as well as other receptors, but the events following the internalization of these complexes, which use apolipoprotein E (apoE) as their ligand for receptor capture, have not been defined. There is evidence that apoE-containing beta-very low density lipoproteins follow differential intracellular routing depending on their size and apoE content and that apoE internalized with lipoproteins can be resecreted by cultured hepatocytes and fibroblasts. In the present studies, we addressed the question of apoE sparing or recycling as a physiologic phenomenon. Remnant lipoproteins (d < 1.019 g/ml) from normal mouse plasma were iodinated and injected into normal C57BL/6 mice. Livers were collected at 10, 30, 60, and 120 min after injection, and hepatic Golgi fractions were prepared for gel electrophoresis analysis. Golgi preparations were analyzed for galactosyltransferase enrichment (>40-fold above cell homogenate) and by appearance of the Golgi stacks and vesicles on electron microscopy. Iodinated apoE was consistently found in the Golgi fractions peaking at 10 min and disappearing by 2 h after injection. Although traces of apoB48 were present in the Golgi fractions, the apoE/apoB ratio in the Golgi was 50-fold higher compared with serum. Quantitatively similar results were obtained when the very low density lipoprotein remnants were injected into mice deficient in either apoE or the LDL receptor, indicating that the phenomenon of apoE recycling is not influenced by the production of endogenous apoE and is not dependent on the presence of LDL receptors. In addition, radioactive apoE in the Golgi fractions was part of d = 1.019-1.21 g/ml complexes, indicating an association of recycled apoE with either newly formed lipoproteins or the internalized complexes. These studies show that apoE recycling is a physiologic phenomenon in vivo and establish the presence of a unique pathway of intracellular processing of apoE-containing remnant lipoproteins.

Animals↗
PubMed1999

Increased cerebral cortical lipid peroxidation and abnormal phospholipids in aged homozygous apoE-deficient C57BL/6J mice.

Aged homozygous apolipoprotein E gene-deficient (apoE -/-) mice have been proposed as an experimental model for the role of human apoE isoforms in Alzheimer's disease (AD). However, results from different laboratories have been in conflict regarding the presence or absence of neurodegeneration in these mice. Moreover, despite apoE being the major lipid trafficking molecule in the central nervous system, there has been no investigation of brain lipid levels in apoE -/- mice. Here we have examined male and female apoE -/- and control mice aged 10 to 12 months, testing the hypothesis that lack of apoE leads to some of the neuropathological changes seen in AD. Our results failed to demonstrate significant neurodegeneration, histopathological changes, or reduction in cerebral cortical synaptophysin in apoE -/- mice. However, we did observe a significant reduction in cerebral cortical phospholipids and their constituent fatty acids, as well as elevated lipid peroxidation products, in apoE -/- mice compared to apoE +/+ mice with the same genetic background. Our results suggest that the brains of aged apoE -/- mice display some of the lipid abnormalities associated with AD; however, these changes alone, at the magnitudes achieved in the apoE -/- mice, do not directly lead to the major neurodegenerative changes of AD.

Aging↗
PubMed1999

Macrophages, lipoprotein metabolism, and atherosclerosis: insights from murine bone marrow transplantation studies.

The macrophage expresses a variety of genes that may contribute to lipoprotein metabolism and atherosclerotic lesion formation. Bone marrow transplantation experiments using gene-targeted mice, both as donors and recipients, provide a useful approach to examine the contribution of macrophage gene expression to lipoprotein metabolism and atherogenesis in vivo. This article describes recent insights into the role of macrophage expression of apolipoprotein E and the LDL receptor gained from bone marrow transplantation studies in the mouse.

Animals↗
PubMed1999

Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.

We previously described a Sardinian family in which the probands had a severe form of hypercholesterolemia, suggestive of familial hypercholesterolemia (FH). However, low density lipoprotein (LDL) receptor activity in fibroblasts from these subjects and LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait. Sitosterolemia and pseudohomozygous hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoprotein (apo) B, sitosterolemia, and cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of LDL in 3 probands from these 2 families. 125I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19+/-0.01 versus 0.36+/-0.03 pools per day, respectively; P<0.001) and a significant increase in the production rate [20.7+/-4.4 versus 14. 0+/-2.4 mg. kg-1. d-1, respectively; P<0.01] of LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99mtechnetium-labeled LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appears to be caused by a selective reduction in hepatic LDL uptake. We propose that in this new lipid disorder, a recessive defect causes a selective impairment of LDL receptor function in the liver.

Adult↗
PubMed1999

Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice.

Atherosclerosis may be viewed as an inflammatory disease process that includes early oxidative modification of LDLs, leading to foam cell formation. This "oxidation hypothesis" has gained general acceptance in recent years, and evidence for the role of lipoxygenases in initiation of, or participation in, the oxidative process is accumulating. However, the relative contribution of macrophage-expressed lipoxygenases to atherogenesis in vivo remains unknown. Here, we provide in vivo evidence for the role of 12/15-lipoxygenase in atherogenesis and demonstrate diminished plasma IgG autoantibodies to oxidized LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis-prone apo E-deficient mice (apo E-/-/L-12LO-/-). In chow-fed 15-week-old apo E-/-/L-12LO-/- mice, the extent of lesions in whole-aorta en face preparations (198 +/- 60 microm2) was strongly reduced (P < 0.001, n = 12) when compared with 12/15-lipoxygenase-expressing controls (apo E-/-/L-12LO+/+), which showed areas of lipid deposition (15,700 +/- 2,688 microm2) in the lesser curvature of the aortic arch, branch points, and in the abdominal aorta. These results were observed despite cholesterol, triglyceride, and lipoprotein levels that were similar to those in apo E-deficient mice. Evidence for reduced lesion development was observed even at 1 year of age in apo E-/-/L-12LO-/- mice. The combined data indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and suggest that inhibition of this enzyme may decrease disease progression.

Animals↗