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Biomedical subjects

G Franceschini

Publications and source records attributed to G Franceschini.

At least 37 records · Page 2Linked to original sources
PubMed1997

Inhibition of VCAM-1 expression in endothelial cells by reconstituted high density lipoproteins.

Plasma-derived high density lipoproteins (HDL) were found to inhibit cytokine-induced expression of endothelial cell adhesion molecules. Here we used apolipoprotein-specific reconstituted HDL (rHDL) made with phosphatidylcholine (PC) and three different apolipoproteins to identify the HDL components involved in this effect. rHDL containing apolipoprotein A-I (apoA-I), the disulfide-linked form of the apoA-IMilano variant, or apoA-II, were all effective in inhibiting the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 in TNF alpha- or LPS-stimulated HUVEC. The inhibition was concentration dependent in the range of 0.1-1.0 mg/ml (protein). PC liposomes slightly depressed TNF alpha-induced VCAM-1 expression (16% vs 43-50% for the various rHDL), whereas the lipid-free apolipoproteins had no effect. The protein component of HDL is involved in the inhibition of VCAM-1 expression in HUVEC through a rather unspecific mechanism, as three apolipoproteins with remarkably different primary structure display very similar activity.

Apolipoprotein A-I↗
PubMed1997

Denaturation and self-association of apolipoprotein A-I investigated by electrophoretic techniques.

Purified human apolipoprotein A-I (apoA-I), when run across a transverse urea gradient at alkaline pH, gives a complex pattern characterized by a number of parallel sigmoidal curves, in which the transition between high- and low-mobility forms, i.e. from folded to unfolded structure, occurs between 1.1 and 3.2 M urea. Size differences appear to be the major cause of this isomerism. When migrated across a wide pH range in the presence of varying amounts of urea to display its titration curve, apoA-I is resolved into two pairs of bands, running parallel in the neutral to basic pH region while merging at acidic pH; such a finding does not correlate with a differential exposure of His residues, as shown by diethyl pyrocarbonate titration. Ferguson plot analysis, confirmed by cross-linking experiments, demonstrates a gradual shift from higher to lower mass aggregates as the urea concentration is raised; the monomeric form undergoes denaturation by swelling to an approximately 50% larger hydrodynamic volume than in its native state. At alkaline pH, where apoA-I exists as aggregated species, disaggregation and unfolding appear to happen at once, the larger aggregates being less stable than the smaller ones. At acidic pH, apoA-I does not form aggregates and has little secondary structure; unfolding is then a progressive rather than a cooperative process.

Apolipoprotein A-I↗
PubMed1997

Activation of lecithin cholesterol acyltransferase by a disulfide-linked apolipoprotein A-I dimer.

Apolipoprotein A-IMilano is a molecular variant of apoA-I, containing the Arg173-->Cys substitution that forms a disulfide linked homodimer (A-IM/A-IM). To assess the effect of this structural modification on a major function of the apolipoprotein, its activation of lecithin cholesterol acyltransferase (LCAT), we prepared well-defined complexes of A-IM/A-IM and apoA-I with phospholipids and cholesterol and compared their reactivities with LCAT. Particles with A-IM/A-IM had very similar diameters to apoA-I particles (7.8 and 12.5 nm) but had distinct apolipoprotein and phospholipid contents and protein secondary structures; they bound LCAT with comparable affinities, but were less efficient substrates for the enzyme (40 to 70% less reactive). We conclude that the local structural constraints in A-IM/A-IM do not prevent the formation of well-defined complexes with phospholipids and do not influence the binding of the enzyme to the particles, but have an inhibitory effect on LCAT activation.

Apolipoprotein A-I↗
PubMed1997

Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content.

Plasma-membrane composition plays a crucial role in most of the cellular functions that depend on membrane processes. In virtually all cell types the proteolytic processing of Alzheimer amyloid precursor protein (APP) to generate soluble APP (sAPP) is believed to occur at the plasma membrane or in its immediate proximity. Alteration of this metabolic pathway has been linked to the pathogenesis of Alzheimer's disease. We analysed the effect of membrane cholesterol enrichment on APP metabolism. Incubation of COS cells with increasing concentrations of non-esterified cholesterol carried by rabbit beta-very low-density lipoprotein caused a dose-dependent inhibition of sAPP release: 70% inhibition with 10 microg/ml non-esterified cholesterol. A less pronounced inhibitory effect was observed on treatment with human low-density lipoprotein. Inhibition of sAPP release was independent of receptor-mediated lipoprotein metabolism since simultaneous treatment with chloroquine did not modify the effect of lipoprotein treatment. In addition, treatment with cholesterol dissolved in either ethanol or methyl-beta-cyclodextrin elicited the same effect. Excess non-esterified cholesterol did not cause cell toxicity. Cell cholesterol mass inversely correlated with sAPP release. Progesterone, which inhibits shuttling of non-esterified cholesterol between the plasma membrane and intracellular pools, had no effect on the inhibition of sAPP release from cholesterol-loaded cells, providing indirect evidence that cholesterol may act at the plasma membrane.

Amyloid beta-Protein Precursor↗
PubMed1997

Clinical evaluation of probucol in hypercholesteremia: individual lipoprotein responses and inhibitory effect on carotid atherosclerosis progression.

Probucol treatment has been evaluated in 140 patients with hypercholesterolemia attending a single Lipid Clinic, in an attempt to identify the relations between lipid/lipoprotein responses and patient characteristics. Probucol was administered as a single drug at the standard dose (0.5 g tablets b.i.d.) for at least 6 months. One-hundred (71%) patients displayed a reduction of low-density lipoprotein cholesterol (LDL-C), which was significantly correlated with the baseline LDL-C level (r = 0.64; p < 0.0001). Most of the patients (90%) also responded with a reduction of high-density lipoprotein cholesterol (HDL-C); the HDL-C reduction was also directly related to baseline HDL cholesterolemia (r = 0.67, p < 0.0001). A highly significant correlation was found between the individual LDL-C and HDL-C responses. Eleven patients who continued with probucol treatment had a B-mode ultrasonographic investigation performed at baseline and after 24 months. No changes in carotid mean and maximal intimal-medial thickness were recorded, in contrast to an increase (i.e., indicative of atherosclerosis progression) in matched patients with hypercholesterolemia receiving other lipid-lowering regimens. Our report underlines that probucol can still provide a valuable option for the treatment for hypercholesterolemia, being particularly effective in patients with a combined increase of LDL-C and HDL-C levels.

Adult↗
PubMed1997

High density lipoprotein and coronary heart disease: insights from mutations leading to low high density lipoprotein.

Hypoalphalipoproteinemia can result from defects in the genes encoding apolipoprotein A-I, the major protein component of HDL, or enzymes that are critical for the formation/maturation of mature HDL. Recent information contradicts earlier findings, suggesting that most of the affected subjects are at increased risk of developing coronary heart disease, independent of the mutated gene. A possible exception is represented by mutations in the apolipoprotein A-I gene leading to structural variants, that might even exert a protective effect against atherosclerosis.

Apolipoprotein A-I↗
PubMed1997

High density lipoprotein particle size restriction in apolipoprotein A-I(Milano) transgenic mice.

Human carriers of apolipoprotein A-I(Milano) (Arg173 --> Cys substitution in apolipoprotein A-I) are characterized by an HDL deficiency in which small, dense HDL accumulate in plasma. Because affected individuals are heterozygous for this mutation, the full impact of apolipoprotein A-I(Milano) (apoA-I(Milano)) on HDL-cholesterol metabolism is unknown. In this study, apoA-I(Milano) transgenic mice were used to evaluate the extent of apoA-I(Milano) dimerization and HDL particle size restriction in the absence of wild-type apoA-I. Murine apoA-I knockout mice were utilized to express apoA-I(Milano) and human apoA-II in the presence of wild-type, human apoA-I (apoA-IMilano/A-Iwt/A-II) and in its absence (apoA-IMilano/A-II). Plasma HDL-cholesterol concentrations were similar (30 mg/dl) in both lines of apoA-I(Milano) transgenic mice. In the apoA-IMilano/A-Iwt/A-II phenotype, 14% of the apoA-I(Milano) formed homodimers and 33% formed heterodimers with apoA-II. ApoA-I(Milano) homodimers increased by 71% in the apoA-IMilano/A-II transgenics and was associated with an abundance of small, 7.6-nm HDL3-sized particles compared to the 9.5, 8.3, and 7.6-nm-sized particles in apoA-IMilano/A-Iwt/A-II mice. The unesterified cholesterol/cholesteryl ester mole ratio of HDL was elevated by 45% in apoA-IMilano/A-Iwt/A-II mice and by 90% in apoA-IMilano/A-II transgenics compared to wild-type (human apoA-I/A-II). Both apoA-I(Milano) transgenics possessed normal levels of plasma LCAT activity, but endogenous cholesterol esterification rates were reduced by 50% compared to controls. Thus, HDL particle size restriction was not the result of impaired LCAT activation; rather, dimerization of apoA-I(Milano) limited the esterification of cholesterol on endogenous HDL. In the absence of wild-type apoA-I, the more extensive dimerization of apoA-I(Milano) severely limited cholesteryl ester accumulation on plasma HDL accounting for the abundance of small, 7.6-nm HDL3 particles in apoA-IMilano/A-II mice.

Animals↗
PubMed1996

Cholesterol efflux from Fu5AH hepatoma cells induced by plasma of subjects with or without coronary artery disease and non-insulin-dependent diabetes: importance of LpA-I:A-II particles and phospholipid transfer protein.

We measured the capacity of human plasma to induce cholesterol efflux from Fu5AH rat hepatoma cells in four groups of men with or without non-insulin-dependent diabetes mellitus (NIDDM) and coronary artery disease (CAD). Plasma from men with both NIDDM and CAD (n = 47) had the lowest efflux capacity (17.3 +/- 3.6%) whereas healthy control subjects with neither diabetes nor CAD (n = 25) had the highest capacity (19.8 +/- 3.4%). The groups with CAD but no diabetes (n = 44) and with NIDDM but no CAD (n = 35) had intermediate efflux values (18.5 +/- 3.8 and 18.5 +/- 3.9%, respectively). In a 2 x 2 factorial ANOVA, the differences were significant with respect to the presence of CAD (P = 0.038) and NIDDM (P = 0.041), with no interaction between the factors. The concentration of HDL particles containing apolipoprotein (apo) A-I but no apo A-II (LpA-I) was not related to efflux capacity in univariate or multivariate analyses. A multivariate regression analysis showed that when controlled for the presence of NIDDM and CAD, the concentration of particles containing both apo A-I and apo A-II (LpA-I:A-II) and plasma phospholipid transfer protein activity were both positively, independently, and significantly (P < 0.001) related to cholesterol efflux capacity.

Aged↗
PubMed1996

Human apolipoprotein A-II inhibits the formation of pre-beta high density lipoproteins.

The role of human apolipoprotein A-II (apoA-II) in the remodeling of human high density lipoproteins (HDL) was investigated during incubation of native and reduced-carboxamidomethylated (RCM) HDL3 with a lipoprotein-depleted plasma fraction (LPDP) in the presence of triglyceride-rich particles (TGRP) isolated from Intralipid. Reduction-carboxamidomethylation of HDL3 entirely converts the disulfide-linked apoA-II dimers into monomers, without affecting the structure, composition and particle size distribution of HDL3. Following incubation with LPDP and TGRP, unmodified HDL3 are mainly converted into large, HDL2 particles (diameter: 9.90 +/- 0.07 nm), enriched in triglycerides and depleted of cholesteryl esters. RCM-HDL3 are converted into both large HDL2 (9.86 +/- 0.07 nm) and small (7.53 +/- 0.06 nm) HDL3. The small products are protein-rich and cholesterol-poor, and consist of two different particles: a component with pre-beta mobility, containing only apoA-I, and a component with alpha mobility, containing both apoA-I and apoA-II. Kinetic studies suggest that a two-step process is involved in the formation of small, pre beta-HDL3, by which changes in lipid composition cause alterations in lipoprotein structure/stability, favoring the dissociation of apolipoproteins and reduction of particle size. These findings indicate that apolipoprotein structure is a major determinant of HDL remodeling, apoA-II potentially counteracting the anti-atherogenic properties of apoA-I by inhibiting the formation of small, pre-beta-migrating HDL.

Adult↗
PubMed1996

The molecular structure of apolipoprotein A-II modulates the capacity of HDL to promote cell cholesterol efflux.

The influence of apolipoprotein A-II (apoA-II) molecular structure on the capacity of high density lipoproteins (HDL) to promote cellular cholesterol efflux was investigated in cultured mouse peritoneal macrophages (MPM). Conversion by reduction and carboxamidomethylation of the naturally occurring dimeric apoA-II to its monomeric form in both native or reconstituted HDL did not change apolipoprotein secondary structure and lipoprotein size/composition. All particles containing monomeric apoA-II, i.e., native HDL3 or reconstituted HDL with or without apoA-I, showed a higher ability to promote cholesterol efflux originating from plasma membrane and intracellular stores, compared to particles containing dimeric apoA-II. These findings indicate that apolipoprotein molecular structure is a major determinant of HDL capacity to promote cholesterol efflux from cells.

Animals↗
PubMed1996

Plasma lipoprotein(a) is an independent factor associated with carotid wall thickening in severely but not moderately hypercholesterolemic patients.

BACKGROUND AND PURPOSE: To evaluate whether high levels of low-density lipoprotein cholesterol (LDL-C) may promote the atherogenic effect of lipoprotein(a) [Lp(a)], we investigated the association between elevated Lp(a) levels and thickening of intima plus media in the common carotid artery (CC-IMT) in patients with different degrees of hypercholesterolemia. METHODS: One hundred type II hypercholesterolemic patients and 25 normolipidemic subjects were selected for the study. Plasma lipid and lipoprotein levels were determined enzymatically; Lp(a) levels were determined by enzyme-linked immunosorbent assay. An Lp(a) concentration > 30 mg/dL was arbitrarily considered a risk factor. For each patient mean CC-IMT was determined by B-mode ultrasound; in 60 patients and in the 25 control subjects, the maximal IMT in the entire carotid tree was also determined. RESULTS: CC-IMT values were higher in hypercholesterolemic patients with plasma Lp(a) levels > 30 mg/dL than in those with lower levels (P < .01). CC-IMT and maximal IMT directly and independently correlated with plasma levels of Lp(a) (r = .33 and r = .25, respectively; both P < .05). The effect of LDL-C concentrations on the relationship between IMT and Lp(a) was investigated by dividing the patients into quartiles of plasma LDL-C levels. After stratification, CC-IMT significantly correlated with plasma Lp(a) levels in the patients with severe hypercholesterolemia (LDL-C > 5.2 mmol/L) but not in patients in the lowest quartile, ie, those with moderate hypercholesterolemia. No correlation between CC-IMT and Lp(a) was found in normolipidemic control subjects. CONCLUSIONS: Elevated plasma levels of Lp(a) can be considered an additional independent factor associated with thickening of the common carotid arteries in patients with severe hypercholesterolemia but not in those with moderate hypercholesterolemia or in normocholesterolemic subjects.

Adult↗
PubMed1995

Association of lipoprotein(a) with atherothrombotic events and fibrinolytic variables. A case-control study.

Elevated plasma levels of lipoprotein(a) [Lp(a)] have been associated with an increased risk of cardiovascular disease. The aim of the present study was to investigate whether Lp(a) plasma levels were associated with subsequent ischemic events and with fibrinolytic variables in patients with established atherosclerotic disease enrolled in the prospective PLAT study. Lp(a) levels and fibrinolytic variables in 37 atherosclerotic patients who subsequently developed an atherothrombotic event during the first year of follow-up (cases) were compared with those in paired controls, matched for age, sex, diagnosis at enrollment and lipid pattern, who remained free from vascular events during the same time frame. Median and mean Lp(a) levels were similar in cases (6.05 mg/dl; 13.8 +/- 19.4 mg/dl) and controls (6.05 mg/dl; 17.1 +/- 21.6 mg/dl). In the whole group plasma Lp(a) levels correlated significantly with the increase of t-PA antigen (r = 0.368; p = 0.002) and fibrinolytic activity (r = 0.410; p = 0.001) induced by venous stasis but not with baseline fibrinolytic variables. These findings indicate that in patients with established atherosclerotic disease Lp(a) may interfere in vivo with the fibrinolytic process but is not predictive of subsequent ischemic events.

Adult↗
PubMed1995

Effect of gemfibrozil treatment in hypercholesterolemia on low density lipoprotein (LDL) subclass distribution and LDL-cell interaction.

Gemfibrozil, a widely used fibric acid derivative, corrects hypercholesterolemia in a non-negligible fraction of patients. To investigate the mechanism of the cholesterol-lowering activity of fibric acids, a study was performed in 12 type IIa hyperlipidemic patients treated with gemfibrozil for 12 weeks. Changes in low density lipoprotein (LDL) structure and composition, agonist capacity of LDL against the LDL-receptor in human skin fibroblasts, LDL-receptor activity in mononuclear cells, lecithin:cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activity, were evaluated. Plasma total and LDL cholesterol levels decreased by 17% and 20% after 12 weeks of treatment, the reduction being directly correlated with the baseline levels (r = 0.75 and 0.78, respectively). The mean LDL diameter increased significantly, from 25.5 to 26.1 nm, while the relative content of small LDL particles (< 25.1 nm) increased from 23.4% to 32.8% of total LDL. Neither the apolipoprotein (apo) B secondary structure nor the affinity of LDL for the LDL-receptor of fibroblasts were affected. The LDL-receptor activity in patients' mononuclear cells increased 3-fold, the rise being unrelated to the plasma cholesterol reduction. LCAT activity did not change, while CETP activity was reduced by 25% (P = 0.13) after treatment. These findings indicate that gemfibrozil causes significant changes in LDL structure that do not, however, affect the LDL interaction with peripheral cells.

Adult↗
PubMed1995

Gene dose of the epsilon 4 allele of apolipoprotein E and disease progression in sporadic late-onset Alzheimer's disease.

A strong association has been described in cross-sectional studies between the epsilon 4 allele of the apolipoprotein E and late-onset Alzheimer's disease (LOAD). This study addresses the relationship between disease progression and the epsilon 4 allele in 62 sporadic LOAD (onset at age 70 and over) patients. Disease progression was estimated retrospectively with the Mini-Mental State Examination (MMSE) amounting to 4.7, 3.8, and 2.2 points per year (sex-adjusted test for trend: p = 0.01) and with the Clinical Dementia Rating (CDR) to 0.76, 0.67, and 0.42 units per year (p = 0.03) in -/-, epsilon 4/-, and epsilon 4/epsilon 4 patients. The proportion of patients with fast progression decreased (p < or = 0.005) and with slow progression increased (p = 0.002) with increasing epsilon 4 gene dose. These findings were confirmed in a smaller sample of 28 patients for whom longitudinal assessments of MMSE were available and when nonlinear progression of the disease was accounted for in a stratified analysis. These data suggest that disease duration might be longer in epsilon 4 carriers and that this might at least partly account for the cross-sectional association between the epsilon 4 allele and LOAD.

Age of Onset↗
PubMed1995

Microsomal enzyme inducers raise plasma high-density lipoprotein cholesterol levels in healthy control subjects but not in patients with primary hypoalphalipoproteinemia.

In this study we compared the ability of phenytoin, a microsomal enzyme inducer, to raise plasma high-density lipoprotein (HDL) levels in normolipidemic subjects and patients with primary hypoalphalipoproteinemia. In healthy control subjects, phenytoin caused a dose-dependent increase of plasma HDL, HDL2, and HDL3 cholesterol levels, up to 40% to 50%. Minor changes were recorded in the plasma concentrations of apolipoprotein (apo) A-I and apo A-II; the plasma level of the cholesteryl ester transfer protein (CETP) decreased by 42%. In contrast, none of the patients with hypoalphalipoproteinemia had changes in plasma HDL, HDL2, or HDL3 cholesterol, apo A-I, apo A-II, or CETP levels. These findings indicate that microsomal enzyme inducers are unsuitable to increase plasma HDL levels in high-risk patients with primary hypoalphalipoproteinemia, and they disclose a new mechanism, that is, decreased CETP-mediated transfer of cholesterol out of HDL, for the HDL-raising effect of microsomal enzyme inducers in healthy individuals.

Aged↗
PubMed1995

Therapy with HMG CoA reductase inhibitors: characteristics of the long-term permanence of hypocholesterolemic activity.

Treatment with hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors has gained considerable success in the management of hypercholesterolemia. A large number of studies have shown the efficacy of these drugs in lowering plasma total and low density lipoprotein (LDL) cholesterol levels, but there have been less studies evaluating their effectiveness in standard clinical practice, particularly relating to the maintenance of hypocholesterolemic activity. In the present study, the long-term effectiveness of HMG CoA reductase inhibitors has been tested in 177 patients with familial hypercholesterolemia (FH) who had been on statin therapy (simvastatin or pravastatin) for at least 12 months and up to 5 years or longer. The mean 'dose normalized' LDL cholesterol reduction in the whole group was around 20%. However, in spite of a generally good efficacy of both statins in lowering total and LDL cholesterol, a wide variety of responses, either after short- or long-term treatment, was noted. Individual responses were calculated and patients classified into three different groups: (a) responders, (b) non-responders, and (c) response losers. Of the 177 patients, 4% did not respond to treatment and a further 10% showed an initial unsatisfactory response (LDL cholesterol reduction < or = 10%). Another 10% experienced a progressive loss of response over time. There appeared to be little difference between the two treatments in the long-term efficacy and no predictive index could be established. Treatment with HMG CoA reductase inhibitors is generally effective and well tolerated, but a non-negligible number of patients may show a primary non-response or a progressive loss of response.

Cholesterol↗