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Biomedical subjects

G Franceschini

Publications and source records attributed to G Franceschini.

At least 55 records · Page 3Linked to original sources
PubMed1995

Triglycerides are major determinants of cholesterol esterification/transfer and HDL remodeling in human plasma.

Lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are responsible for the esterification of cell-derived cholesterol and for the transfer of newly synthesized cholesteryl esters (CE) from HDL to apoB-containing lipoproteins in human plasma. LCAT and CETP are also crucial factors in HDL remodeling, a process by which HDL particles with a high capacity for cell cholesterol uptake are generated in plasma. In the present study, cholesterol esterification and transfer were evaluated in 60 patients with isolated hypercholesterolemia (HC, n = 20) and isolated (HTG, n = 20) or mixed hypertriglyceridemia (MHTG, n = 20) and in 20 normolipidemic healthy individuals (NL). Cholesterol esterification rate (CER) and net CE transfer rate (CETR) were measured in whole plasma. LCAT and CETP concentrations were determined by specific immunoassays. HDL remodeling was analyzed by monitoring changes in HDL particle size distribution during incubation of whole plasma at 37 degrees C. Mean CER and CETR were 48% and 73% higher, respectively, in hypertriglyceridemic (HTG + MHTG) versus normotriglyceridemic individuals. HDL remodeling was also significantly accelerated in plasma from hypertriglyceridemic patients. Strong positive correlations were found in the total sample between plasma and VLDL triglyceride levels and CER (r = .722 and r = .642, respectively), CETR (r = .510 and r = .491, respectively), and HDL remodeling (r = .625 and r = .620, respectively). No differences in plasma LCAT and CETP concentrations were found among the various groups except for a tendency toward higher CETP levels in hypercholesterolemic patients (+51% in MHTG and +20% in HC) versus control subjects (NL). By stepwise regression analysis, VLDL triglyceride level was the sole significant predictor of CER and CETR and contributed significantly together with baseline HDL particle distribution to HDL remodeling. These results indicate that plasma triglyceride level is a major factor in the regulation of cholesterol esterification/transfer and HDL remodeling in human plasma, whereas LCAT/CETP concentrations play a minor role in the modulation of reverse cholesterol transport.

Carrier Proteins↗
PubMed1995

Recombinant apolipoprotein A-IMilano dimer inhibits carotid intimal thickening induced by perivascular manipulation in rabbits.

Apolipoprotein A-IMilano (apoA-IM), a natural variant of apolipoprotein A-I (apoA-I), confers to the carriers a significant protection against vascular disease. The antiatherogenic activity of a recombinant disulfide-linked apoA-IM dimer (rA-IM/A-IM) was analyzed in vivo by evaluating its effect on neointimal formation induced by periarterial manipulation in 1% cholesterol-fed rabbits. A flexible collar was applied around the carotid artery 21 days after the beginning of the dietary regimen, and animals were killed 10 days later. Rabbits were injected five times with reconstituted high-density lipoprotein containing egg phosphatidylcholine (EPC) and rA-IM/A-IM (119 mg EPC + 40 mg protein per dose) or with EPC liposomes (119 mg EPC per dose) beginning either 5 days before or at the day of collar positioning. Neither treatment affected plasma cholesterol levels. A significant intimal thickening was observed in control animals; the intima-to-media (I/M) ratio was 0.63 +/- 0.11 versus 0.03 +/- 0.05 for the sham-operated contralateral arteries. Neointimal formation was markedly inhibited in animals pretreated with rA-IM/A-IM before lesion induction (I/M, 0.26 +/- 0.19) but not in those in which treatment began the day of collar insertion (I/M, 0.74 +/- 0.14). EPC liposomes did not affect neointimal formation (I/M, 0.50 +/- 0.14 and 0.51 +/- 0.07 in the two treatment groups). Proliferation of smooth muscle cells, assessed by direct incorporation of bromo-2'-deoxyuridine (BrdU) into replicating DNA, was reduced by approximately 30% and 75% in the intimal and medial tissues of rA-IM/A-IM-pretreated rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Drug control of reverse cholesterol transport.

Reverse cholesterol transport identifies a series of metabolic events resulting in the transport of excess cholesterol from peripheral tissues to the liver. High-density lipoproteins (HDL) are the vehicle of cholesterol in this reverse transport, a function believed to explain the inverse correlation between plasma HDL levels and atherosclerosis. An attempt to stimulate, by the use of drugs, this transport process may hold promise in the prevention and treatment of arterial disease. Among the agents affecting lipoprotein metabolism, only probucol exerts significant effects on reverse cholesterol transport, by stimulating the activity of the cholesteryl ester transfer protein and, consequently, altering HDL subfraction composition/distribution. Another approach to the stimulation of reverse cholesterol transport consists of raising plasma HDL levels; studies in animals, either by exogenous supplementation or by endogenous overexpression, have shown a consistent benefit in terms of atherosclerosis regression and/or non-progression. Thus, it is time to consider different future treatments of atherosclerosis, combining the classical lipid-lowering treatments with innovative methods to promote cholesterol removal from the arterial wall.

Animals↗
PubMed1994

Pravastatin effectively lowers LDL cholesterol in familial combined hyperlipidemia without changing LDL subclass pattern.

Familial combined hyperlipidemia (FCHL) is the most common genetic lipid disorder among young survivors of myocardial infarction. Elevations of plasma total and low-density lipoprotein (LDL) cholesterol and the prevalence of small, dense LDL particles are both involved in the high coronary risk of FCHL patients. We investigated the ability of pravastatin to favorably correct plasma lipid and lipoprotein levels and LDL structure in FCHL patients. Twelve patients with FCHL, documented by studies of first-degree relatives, received pravastatin (40 mg/d) for 12 weeks. Pravastatin significantly lowered plasma total and LDL cholesterol levels by 21% and 32%, respectively. Triglyceride levels did not change, and apolipoprotein B (apoB) concentrations decreased by 9% (P = NS). High-density lipoprotein (HDL) cholesterol increased by 6% because of a significant 73% rise of HDL2 cholesterol. LDL were smaller (diameter, 24.5 +/- 0.5 nm), less buoyant, and apoB-rich (cholesteryl ester-apoB ratio, 1.64 +/- 0.46) in the selected patients compared with patients with familial hypercholesterolemia or healthy control subjects. LDL became even smaller (23.8 +/- 0.6 nm) and richer in apoB (cholesteryl ester-apoB ratio, 1.27 +/- 0.52) after pravastatin treatment. Although pravastatin favorably altered plasma lipid and lipoprotein levels in FCHL patients, the abnormal LDL particle distribution and composition were not affected. Because of the apparent resistance of the small, dense LDL to drug-induced modifications, a maximal lipid-lowering effect is needed to reduce coronary risk in FCHL patients.

Adult↗
PubMed1994

[Pharmacological control of heart rate].

Heart rate, an important risk factor of coronary mortality, is highly correlated with numerous anthropometric and biochemical variables: height, body weight and hyperlipidemia; it varies, furthermore, with smoking and age and can be modified during pharmacotherapy for hypertension. From meta-analyses on different cardiovascular treatments, given after coronary events, only the efficacy of drugs significantly reducing heart rate is borne out (beta-blockers with sympathomimetic activity, or calcium-antagonists with a prevalent vasodilatory action do not provide a protective effect). Among calcium-antagonists, while the mechanism of action is similar at the cell level (delay of opening of voltage-operated slow channels), the distribution of activity within the vascular system varies markedly. Dihydropyridines (e.g., nifedipine) exert a dominant peripheral effect, with consequent vasodilation, whereas phenylalkylamines (verapamil) have both peripheral vasorelaxant and cardiac negative chronotropic activity, because of a reduced sinus node action potential. A relative tachycardia may occur with dihydropyridines, secondary to the activation of baroreceptors; the compensatory heart mechanism operated by verapamil antagonizes this reflex tachycardia. The activity of verapamil on the atrioventricular conduction allows both a slowing of functional recovery of the channel in hyperexcitable conditions (supraventricular tachycardia), and, moreover, increased diastolic intervals, with consequent improvement of coronary flow. New molecules can selectively reduce the sinus node activity without exerting other effects (hypotensive, anti-arrhythmic). From a comparative evaluation of these molecules with verapamil, it clearly emerges how this latter can provide a more acceptable pharmacodynamic profile, both for the hypotensive activity, and also for the control of reflex tachycardia, with a consequently improvement of coronary flow.

Adrenergic beta-Antagonists↗
PubMed1993

Pharmacological control of hypertriglyceridemia.

Hypertriglyceridemia has been recently recognized as a vascular risk factor, based on both clinical and experimental findings. Epidemiological studies clearly showed that elevated plasma triglycerides in subjects with low high-density lipoprotein (HDL) cholesterol (<35 mg/dl) and/or a low-density lipoprotein (LDL)/HDL cholesterol ratio > 5 are associated with an elevated risk for coronary heart disease (CHD), while intervention studies indicate that triglyceride lowering with drugs may lead to a significant CHD reduction. Elevated blood triglycerides are associated with major alterations in the structure/function of plasma lipoproteins, which become more atherogenic, and with abnormalities in the clotting system, which may predispose to coronary thrombosis. New criteria for the classification of hypertriglyceridemias and a stepwise approach to the management of patients with elevated plasma triglycerides have been recently developed. Nonpharmacological interventions, i.e., weight reduction, alcohol and smoking cessation, and physical exercise, are the first-line actions to control hypertriglyceridemia. Drug therapy should be considered when the nonpharmacological approaches are ineffective or inadequate. Fibric acid derivatives and nicotinic acid (and its derivatives) are the drugs of choice when treating hypertriglyceridemic patients; n-3 fatty acids (fish oil) and metformin (especially in diabetic patients) represent additional therapeutic agents.

Body Weight↗
PubMed1993

Plasma triglycerides and lipoprotein(a): inverse relationship in a hyperlipidemic Italian population.

The relationship between plasma lipoprotein(a) (Lp(a)) levels and other clinical/biochemical variables was investigated in 1200 consecutive hyperlipidemic patients. Plasma Lp(a) concentrations were measured by a sandwich-ELISA method, while the patients were either on diet or diet plus lipid-lowering drugs; 38% of them had a plasma Lp(a) level > 30 mg/dl. The median plasma Lp(a) concentration and the frequency of Lp(a) > 30 mg/dl were significantly lower in individuals with severe hypertriglyceridemia vs. hypercholesterolemics (HC) or mixed hyperlipidemics (M-HLP), but similar to normolipidemic healthy controls. Patients with isolated moderate hypertriglyceridemia had Lp(a) levels intermediate between HC and M-HLP subjects. The in vitro addition of triglyceride-rich lipoproteins to normotriglyceridemic plasma did not affect the Lp(a) measurement. Plasma Lp(a) concentrations in the whole hyperlipidemic population correlated negatively with triglycerides and positively with total cholesterol, HDL-cholesterol and age, being unrelated to either body mass index or lipid-lowering treatment. In HC patients, the presence of tendon xanthomas was associated with twofold higher Lp(a) levels. These findings argue for a regulatory role of triglycerides on plasma Lp(a) levels in hyperlipidemic patients.

Adult↗
PubMed1993

Mechanisms of high-density lipoprotein reduction after probucol treatment: changes in plasma cholesterol esterification/transfer and lipase activities.

Probucol treatment results in a significant reduction of plasma high-density lipoprotein (HDL) levels. Since the remodeling of HDL within the plasma compartment is a crucial determinant of HDL levels, the activities of several factors participating in the process, ie, lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and lipoprotein and hepatic lipases (LPL, HL), were evaluated in 15 hypercholesterolemic patients treated with probucol (1 g/d) for 8 weeks. Drug treatment was associated with significant reductions of HDL cholesterol ([HDL-C] -32%), HDL2-C (-65%), HDL3-C (-22%), apolipoprotein (apo)A-I (-27%), and apo A-II (-11%) levels and with the accumulation of small HDL in plasma. CETP activity increased by 48%, with minor changes in LCAT (-7%), LPL (+4%), and HL (-7%) activities. By linear regression analysis, CETP activity correlated inversely with HDL-C, HDL2-C, and apo A-I levels (r = -.63, -.52, and -.73, respectively) and with HDL particle size. In multivariate analysis, CETP activity was the strongest predictor of HDL-C levels, apo A-I levels, and HDL particle size. The hypothetical mechanism of probucol is a stimulation of CETP activity, resulting in the formation of triglyceride (TG)-enriched HDL. These are acted on by HL, leading to the accumulation of small HDL in plasma.

Apolipoprotein A-I↗
PubMed1993

Increased postprandial lipemia in Apo A-IMilano carriers.

Plasma lipid/lipoprotein changes were monitored after a fat load (65 g fat per square meter body surface area) in six carriers of the apolipoprotein A-IMilano (A-IM) variant and six age- and sex-matched control subjects. The magnitude of postprandial lipemia, calculated as the area under the curve (AUC) described by plasma triglyceride (TG) level versus time, was threefold higher in the A-IM carriers; however, after correction for the different baseline TG levels, it was similar to control subjects. Moreover, the magnitude of postprandial lipemia was positively correlated with baseline TG in both A-IM carriers (r = 0.77) and control subjects (r = 0.80), indicating that fasting TGs are a major determinant of postprandial response in all subjects. Postprandial lipemia was also inversely correlated with high density lipoprotein (HDL) and HDL2 cholesterol in both groups (A-IM, r = -0.81 and -0.79; control subjects, r = -0.87 and -0.94). Different from those in control subjects, the plasma apo A-I levels in the A-IM carriers decreased progressively while apo B increased up to 4 hours but decreased thereafter. Postprandial rises of low density lipoprotein TG but not of HDL-TG AUC were significantly higher in the A-IM carriers, even after normalization for the different fasting concentrations. These data show that the low plasma HDL levels of A-IM carriers, which are secondary to a primary structural alteration of the major HDL apolipoprotein, are associated with elevated fasting and postprandial TG levels and an anomalous postprandial redistribution of TG among lipoprotein classes.

Adult↗
PubMed1993

In vivo metabolism of a mutant form of apolipoprotein A-I, apo A-IMilano, associated with familial hypoalphalipoproteinemia.

Apo A-IMilano is a mutant form of apo A-I in which cysteine is substituted for arginine at amino acid 173. Subjects with apo A-IMilano are characterized by having low levels of plasma HDL cholesterol and apo A-I. To determine the kinetic etiology of the decreased plasma levels of the apo A-I in these individuals, normal and mutant apo A-I were isolated, radiolabeled with either 125I or 131I, and both types of apo A-I were simultaneously injected into two normal control subjects and two subjects heterozygous for apo A-IMilano. In the normal subjects, apo A-IMilano was catabolized more rapidly than the normal apo A-I (mean residence times of 5.11 d for normal apo A-I vs. 3.91 d for apo A-IMilano), clearly establishing that apo A-IMilano is kinetically abnormal and that it has a shortened residence time in plasma. In the two apo A-IMilano subjects, both types of apo A-I were catabolized more rapidly than normal (residence times ranging from 2.63 to 3.70 d) with normal total apo A-I production rates (mean of 10.3 vs. 10.4 mg/kg per d in the normal subjects). Therefore, in the subjects with apo A-IMilano, the decreased apo A-I levels are caused by rapid catabolism of apo A-I and not to a decreased production rate, and the abnormal apo A-IMilano leads to the rapid catabolism of both the normal and mutant forms of apo A-I in the affected subjects.

Adult↗
PubMed1993

Lipoprotein structure in male subjects during in vivo lipolysis: effect of an anti-lipolytic treatment with acipimox.

Plasma free fatty acid (FFA) levels were raised in healthy volunteers by the administration of a fatty meal and epinephrine infusion (0.15 mg/kg per min), to test the hypothesis that enhanced lipolysis might lead to changes in lipoprotein distribution and to the formation of lipoprotein complexes, also impairing the interconversion of high density lipoproteins (HDL). The study was carried out in double-blind conditions in volunteers pre-treated with either placebo or with acipimox, a nicotinic acid analogue with a long-lasting activity. Lipolysis was effectively induced; the treatment with acipimox prevented the rise of free fatty acids (FFA), and it also blunted the triglyceride (TG) increase occurring during the test. Whereas the mean low density lipoprotein (LDL) particle size did not change, the HDL particle distribution showed a progressive shift to smaller particles, both after placebo and after acipimox, the changes in size being maximal 3-7 h after the meal. Evaluation of HDL interconversion in plasma samples incubated at 37 degrees C for 6 h showed the expected accumulation of HDL2a particles, with a parallel decrease of HDL3a; however, this conversion was not affected by the presence of elevated FFA levels and no difference was noted in subjects taking either placebo or acipimox. These clinical data fail to confirm the hypothesis that enhanced lipolysis may lead to dramatic changes in plasma lipoprotein distribution and/or in aggregation or fusion of lipoprotein particles, as reported from in vitro experiments. This study, however, successfully achieved a useful model of exaggerated lipolysis and confirmed the important activity of a low dose nicotinic acid analogue in inhibiting lipolysis.

Adult↗
PubMed1993

Apolipoprotein A-I Milano: sex-related differences in the concentration and composition of apoA-I- and apoB-containing lipoprotein particles.

The presence of apolipoprotein (apo) A-IMilano (A-IM) mutant of apoA-I has a marked effect on plasma lipoproteins of A-IM carriers including variable hypertriglyceridemia, increased levels of very low density lipoproteins (VLDL), slightly elevated levels of triglyceride-enriched low density lipoproteins (LDL) and greatly reduced levels of high density lipoproteins (HDL). To gain further insight into this dyslipoproteinemic syndrome characterized clinically by the absence of coronary artery disease, we have determined the concentration and composition of apoA- and apoB-containing lipoprotein families in four male and four female carriers and corresponding normal controls. Results have shown that A-IM carriers have significantly reduced levels of lipoprotein (LP) A-I (45%), LP-A-I:A-II (60%), and LP-A-II (70%) and significantly increased levels of cholesterol-rich LP-B (67%) and triglyceride-rich LP-B:C, LP-B:C:E, and LP-A-II:B:C:D:E (65%) particles compared to controls. However, there were significant sex-related differences in the levels of apoA-and apoB-containing lipoproteins. Female carriers had significantly higher concentrations of LP-A-I (39 +/- 10 vs. 12 +/- 6 mg/dl) and LP-A-I:A-II (48 +/- 11 vs. 30 +/- 6 mg/dl) than male carriers. Furthermore, female carriers had higher levels of LP-B:C (23 +/- 18 vs. 6 +/- 5 mg/dl) and LP-A-II:B:C:D:E (13 +/- 6 vs. 2.3 +/- 0.8 mg/dl) but lower concentrations of LP-B (103 +/- 52 vs. 152 +/- 54 mg/dl) and LP-B:C:E (5 +/- 2.5 vs. 13 +/- 8 mg/dl) than male carriers. In general, the levels of LP-A-I and LP-A-I:A-II particles correlated positively with the levels of all three types of triglyceride-rich lipoproteins (LP-Bc) and negatively with the levels of LP-B particles. A comparative study of lipoprotein families in several dyslipoproteinemic states characterized by low levels of HDL has indicated that the characteristic lipoprotein particle profile of A-IM carriers results most probably from the selective effect of apoA-IM mutant rather than a general reduction in HDL levels. It appears that increased levels of LP-A-II:B:C:D:E particles, an inefficient substrate for lipoprotein lipase, and structurally defective LP-A-I:A-II particles, the normal acceptors of minor apolipoproteins released during lipolysis of triglyceride-rich lipoproteins, may be the main contributing factors to moderate hypertriglyceridemia characteristic of A-IM carriers.

Adult↗
PubMed1992

Apolipoprotein A-II modulates HDL remodeling in plasma.

Native and reduced-carboxamidomethylated (RCM) HDL3 are incubated with a lipoprotein-depleted plasma fraction in the presence of triacylglycerol-rich particles isolated from Intralipid. Unmodified HDL3 are mainly converted into large HDL2b particles (diameter: 9.84 +/- 0.15 nm); RCM-HDL3 are transformed into both large HDL2b (9.76 +/- 0.10 nm) and small HDL3c (7.68 +/- 0.07 nm). These findings indicate that the apo A-II dimers participate in the remodeling of HDL, by inhibiting the formation of small HDL particles.

Animals↗