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Biomedical subjects

C Napoli

Publications and source records attributed to C Napoli.

At least 91 records · Page 5Linked to original sources
PubMed1997

A simple and rapid purification procedure minimizes spontaneous oxidative modifications of low density lipoprotein and lipoprotein (a).

Usual purification procedures of LDL and Lp(a) require numerous, extensive and prolonged sample handlings: this greatly increases the possibility of spontaneous oxidation. We have developed a method which, making use of two short-run ultracentrifugations in vertical rotors alternated by two rapid column-chromatography steps (SRUC), significantly shortens the preparation time to 3.5 h (LDL) and does not demand additional instrumentation or particular accuracy. Purification of Lp(a) requires a further wheat germ agglutinin chromatographic step, which can be accomplished within 30 min. More importantly, the method significantly reduces spontaneous oxidation as compared with classical isolation procedures. LDL isolated by the standard sequential method exhibits more extensive apolipoprotein B100 degradation, lipid peroxidation, and endogenous antioxidant (vitamin E) loss than the same lipoproteins obtained by means of the SRUC. This procedure may have be particularly valuable in experiments evaluating the effects of oxygen radical-induced modifications, especially in vitro.

Adolescent↗
PubMed1997

Propafenone in the conversion of atrial fibrillation in patients suffering from chronic renal failure.

Propafenone is a class Ic agent for the treatment of atrial arrhythmias with a main hepatic metabolism. This approach might play an important role in the management of atrial arrhythmias in patients with chronic renal failure. The goal of this study was to investigate the effects of propafenone in patients with atrial fibrillation and chronic renal failure. We studied 24 patients with atrial fibrillation that was associated with chronic renal failure. The conversion time was 8.4 +/- 3.2 minutes (range, 5-19 minutes) with intravenous propafenone at 1 mg/kg bolus over 5 minutes. In 21 patients (87%) sinus rhythm was restored and no serious adverse and proarrhythmic effects were noted. Corrected QT interval was not prolonged after conversion (from 0.33+/-0.06 mm to 0.32+/-0.04 mm, p = not significant). Two and 6 months later the cardioversion left atrial size significantly decreased in 19 patients who had been converted to sinus rhythm. The parameters of renal function were unchanged after propafenone therapy. We concluded that: 1) propafenone is active and acts significantly faster in converting atrial fibrillation in patients with chronic renal insufficiency; 2) propafenone administration appears to be safe in patients with chronic renal failure; and 3) left atrial size decreases upon conversion to sinus rhythm as seen at 6-month follow-up.

Anti-Arrhythmia Agents↗
PubMed1997

High prevalence of myocardial ischemia and vasoconstrictive hormonal release in hypertension during chronic renal failure.

OBJECTIVE: Indexes of myocardial ischemia and vasoconstrictive hormonal release were evaluated in order to investigate the difference between essential hypertension and hypertension during chronic renal failure. BACKGROUND: Arterial hypertension induces several cardiovascular alterations that reflect themselves either on the heart and/or on the coronary blood flow enhancing the cardiovascular risk. Since chronic renal failure can influence the neuroendocrine response, various mechanisms involved in hypertension during chronic renal failure are still unclear. High endothelin 1 (ET-1) levels have been found both in arterial hypertension and during chronic renal failure. Interestingly, either ET-1 or catecholamines seem also to be implied in the pathogenesis of myocardial ischemia. METHODS: 20 hypertensive uremic and 20 essentially hypertensive patients underwent echocardiographic wall motion and wall thickening analysis performed at baseline and immediately after the end of exercise. Simultaneously, myocardial perfusion was evaluated by 99mTc-MIBI-SPECT. In addition, plasma norepinephrine and ET-1 concentrations were measured at baseline and at peak exercise. RESULTS: The segmental radionuclide analysis showed a greater ischemic degree in hypertensive uremic patients. Yet, we were able to identify one or more regions of the left ventricle in which both systolic thickening measurements and wall motion after exercise were impaired. After exercise, wall thickening impairment was correlated with both wall motion abnormalities (r = 0.72, p < 0.01) and MIBI ischemic grade (r = 0.82, p < 0.001). Basal and after-exercise plasmatic norepinephrine and endothelin levels were higher in hypertensive uremic than in essentially hypertensive patients. Moreover, there was a significant correlation between increments in norepinephrine concentration and MIBI perfusion defects, and between the increment in ET-1 concentration and both MIBI perfusion defects, or kinetic alterations assessed by wall motion as well as by wall thickening. CONCLUSIONS: This is the first cross-sectional study in which a higher degree of myocardial ischemia has been observed in hypertensive uremic patients combined with an enhanced plasma release of both norepinephrine and ET-1. This phenomenon may contribute to enhance the cardiovascular risk of these patients.

Aged↗
PubMed1997

Prevalence of peripheral arterial disease in an elderly rural population of southern Italy.

Blood pressure was measured at the posterior tibial artery by Doppler ultrasonography in 440 elderly subjects (205 men and 235 women) living in a rural community of Southern Italy, together with the evaluation of traditional risk factors for cardiovascular disease. An ankle/arm systolic pressure ratio below 0.90 was considered as a definite pathological sign of peripheral arterial disease (PAD). About 10% of both men and women had a value below 0.90. Elderly subjects with PAD had higher serum triglyceride levels and a higher ratio between the cholesterol content in atherogenic (VLDL + LDL) versus non-atherogenic (HDL) lipoproteins than subjects free of PAD. The mean blood pressure was also higher in patients with PAD. The prevalence of PAD was much lower than what we have observed in institutionalized old subjects in Southern Italy.

Age Distribution↗
PubMed1997

Mildly oxidized low-density lipoprotein impairs responses of carotid but not basilar artery in rabbits.

BACKGROUND AND PURPOSE: Intracranial blood vessels appear to be relatively resistant to development of atherosclerosis. The goal of this study was to compare effects of mildly oxidized LDL (ox-LDL) on endothelium-dependent responses of intracranial and extracranial arteries in vitro. METHODS: LDL was purified from plasma of healthy subjects and mildly oxidized by means of a xanthine/xanthine oxidase reaction. Contraction of the rabbit basilar and carotid arteries in response to histamine and phenylephrine and relaxation in precontracted vessels to acetylcholine and sodium nitroprusside were evaluated after 30 minutes of exposure to LDL or ox-LDL (100 micrograms/mL). RESULTS: Exposure to LDL had little or no effect on vascular responses. After exposure to ox-LDL, contraction to histamine and phenylephrine and relaxation to acetylcholine were impaired significantly in carotid (P < .05) but not in basilar artery. Relaxation to sodium nitroprusside was not significantly impaired by ox-LDL in the basilar artery. In the carotid artery, relaxation to sodium nitroprusside was significantly impaired by ox-LDL when the vessels were precontracted with phenylephrine but not histamine. Impairment of vascular responses by ox-LDL was prevented by addition of superoxide dismutase, catalase, or dimethylthiourea to the LDL solution before addition of xanthine/xanthine oxidase. CONCLUSIONS: Mildly ox-LDL impairs contraction and endothelium-dependent relaxation in the carotid but not in basilar artery. Thus, intracranial arteries may be relatively resistant to mildly ox-LDL.

Animals↗
PubMed1997

Long-term Treatment With Pravastatin Alone and in Combination With Gemfibrozil in Familial Type IIB Hyperlipoproteinemia or Combined Hyperlipidemia.

BACKGROUND: Pravastatin inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase. It prevents mevalonate synthesis, reducing endogenous cholesterol production, and reduces cholesterol content in the liver, thus resulting in a down-regulation of low-density lipoprotein receptor production. Gemfibrozil reduces very low-density lipoprotein production and low-density lipoprotein-cholesterol level and increases very low-density lipoprotein catabolism. Therefore, it was suggested that combination therapy with both drugs could effect greater reduction of cholesterol levels as compared to pravastatin alone. The present study was carried out to evaluate the efficacy and safety of pravastatin as a monotherapy or in combination with gemfibrozil in the treatment of patients with familial type IIb hyperlipoproteinemia or familial combined hyperlipidemia. METHODS AND RESULTS: Forty-one patients were included in the study. All patients initially followed 6 weeks of hypolipidemic diet; subsequently they were randomized and received either 20 mg once daily of pravastatin alone (n = 13) or 20 mg of pravastatin together with 600 mg of gemfibrozil twice daily (n = 14). As a control, 14 patients were treated with diet only. The treatment lasted 24 months and clinical evaluation and laboratory tests were done at given time points. Both groups of treated patients showed an early reduction (3 months) of total (about 30% P <.01 vs controls), low-density lipoprotein (about 35%, P <.01 vs controls) and very low-density lipoprotein cholesterol levels (about 18%, P = NS). In contrast, high-density lipoprotein cholesterol levels increased significantly in patients treated with pravastatin and gemfibrozil (about 20%, P <.05 vs controls). Pravastatin treatment alone reduced the level of serum triglycerides as efficiently as in combination with gemfibrozil. Data showed a sustained normalization of lipid profile until 24 months. However, this effect was achieved in patients that had rather low levels of triglycerides. During the treatment we did not observe any difference in the incidence of possible drug-related side effects. Severe myopathy or rhabdomyolysis was not observed at the doses of the drugs used in our study. CONCLUSIONS: Therapy with pravastatin and in combination with gemfibrozil resulted in significant and sustained normalization of lipid profile in high-risk patients with familial type IIb hyperlipoproteinemia or familial combined hyperlipidemia.

Journal Article↗
PubMed1997

Low density lipoprotein oxidation and atherogenesis: from experimental models to clinical studies.

Oxidative modifications of low-density lipoproteins (LDL) ("oxidation hypothesis") appears to be the pathophysiologic mechanism implicated in early atherogenesis. Oxidized LDL (ox-LDL) may also induce several pro-atherogenic mechanisms, such as the regulation of vascular tone, by interfering with nitric oxide, the stimulation of cytokines and chemotactic factors (MCP-1, M-CSF, VCAM-1, etc.) and transcription factors (AP1 and NFk beta). These phenomena complicate the spectrum of direct and indirect actions of ox-LDL. The immunogenicity of ox-LDL was used to generate monoclonal antibodies against many epitopes of ox-LDL, such as malondialdehyde-lysine (MDA-2) or 4-hydroxynonenal-lysine (NA59). These antibodies showed the occurrence of ox-LDL in vivo. Another issue is the role of the humoral and cellular immune system in atherogenesis, in particular whether the immune response to ox-LDL enhances or reduces early atherogenesis. Moreover, the induction of autoantibodies against ox-LDL and the recognition by "natural" antibodies, and the use of the those antigens to screen human sera may serve as a marker of atherosclerosis. In this review, we have stressed the importance of methodologic approach in the assessment of LDL-oxidation and the fact that lipoprotein (a) may also undergo oxidative modifications. Several clinical conditions are associated with increased rate of LDL-oxidation. Recently, we have observed the presence of LDL oxidation-specific epitopes in human fetal aortas. Antioxidants studies in primary prevention of atherosclerosis have produced contradictory results. This may be explained in part by the selection of patients who had advanced lesions and were often smokers. New trails suggest that antioxidants be administered early in children. Lastly, antioxidant studies in the secondary prevention of coronary heart disease (CHAOS, WACS, and HOPE) show clear evidence of the benefits of antioxidants in reducing new cardiovascular events.

Animals↗
PubMed1996

Calcium-channel blockers inhibit human low-density lipoprotein oxidation by oxygen radicals.

Previous studies have shown that calcium channel blockers may reduce the development of experimental atherosclerosis, and that nifedipine may slow the progression of coronary atherosclerosis in humans. The mechanisms responsible for this antiatherogenic effect are still unclear. It has been recently proposed that oxygen free radicals can induce the oxidation of human low-density lipoproteins (LDL) and that oxidized LDL may be an atherogenic stimulus. Previous studies in other systems have shown that calcium channel blockers may effectively inhibit oxygen radical-induced lipid peroxidation in vitro. Thus, the aim of the present study was to investigate whether calcium channel blockers may also reduce LDL modifications induced by oxygen radicals. Isolated human LDL were exposed to oxygen radicals generated by CuSO4 (10 microM for 18 hours) after a 30 minute pre-incubation with different concentrations (1-100 microM) of nifedipine, diltiazem, and verapamil. Lipid peroxidation was measured from malonyldihaldehyde (MDA) production. Oxygen radical-induced damage on apolipoprotein-B100 was evaluated by acrylamide and agarose gel electrophoresis. Calcium channel blockers dose-dependently prevented oxidation of both the lipid and protein components of LDL. MDA formation was reduced in LDL pre-incubated with calcium antagonists before exposure to oxygen radicals (% MDA inhibition was 89.8 +/- 6.9 with 30 microM nifedipine, 68.6 +/- 4.9 with 30 microM verapamil, and 65.6 +/- 7.1 with 30 microM diltiazem; p < 0.01 vs. controls). Similarly, apolipoprotein-B100 integrity was preserved against oxygen radical attack in the presence of calcium antagonists. Thus, calcium channel blockers reduce the oxidation of human LDL in vitro. These data suggest that reduced formation of atherogenic oxidized LDL may be an additional mechanism for the antiatherosclerotic effects of calcium channel blockers in vivo.

Analysis of Variance↗
PubMed1996

Relations between vasoactive hormones and diastolic function in hypertensive uraemic patients.

BACKGROUND: Arterial hypertension is a significant risk factor for the high rate of cardiovascular disease in chronic uraemic (CU) patients. Any role that hypertension may play in CU patient outcomes assumes added significance. The elevation of some hormonal factors in early clinical stage could represent a valuable marker of cardiac disease in CU. AIM: This study first investigated the role of several hormones on cardiac diastolic properties in CU patients. Moreover, the study investigated the association of hypertension with both diastolic function and release of vasoactive hormones in CU patients. RESULTS: We have reported that the early impairment of diastolic function is correlated with the elevation of both circulating plasma atrial natriuretic factor and endothelin-1 (ET-1) in hypertensive CU patients. Since the effect of ET-1 on diastolic function is still poorly understood, we have investigated also this issue. In eight additional patients with reduced E/A ratio, but without uraemia, hypertension or chronic heart failure, we have showed a high inverse correlation between the values of E/A ratio and ET-1 plasma concentrations. CONCLUSIONS: These results strongly suggest that the elevation in ET-1 levels was correlated with diastolic dysfunction in man. This phenomenon may have important pathophysiological implications suggesting the possibility of an early therapeutic approach in these patients.

Adult↗
PubMed1996

The role of aging on the control of contractile force by Na(+)-Ca2+ exchange in rat papillary muscle.

BACKGROUND: Sarcolemmal Na(+)-Ca2+ exchange system is believed to be fundamental to the control of cardiac contractility. However, the relation between Na(+)-Ca2+ exchange and the control of contractile force has not been studied in senescent myocardium. METHODS: The role of Na(+)-Ca2+ exchange in the regulation of the cardiac muscle's contractile force was studied in adult and senescent papillary muscles by simultaneously measuring intracellular sodium activity (aNai), action potential, and contractile force while varying extracellular concentration of sodium and/or calcium. RESULTS: Reduction of [Na+]o decreased aNai from 8.0 +/- 1.8 to 4.1 +/- 0.8 in adult (-3.9 mM) and from 8.7 +/- 1.9 to 4.7 +/- 0.9 in senescent (-4.0 mM) papillary muscles, while developed tension (DT) increased by 80.2% in adult and by 135.6% in senescent papillary muscles (p < .01 vs adult). During low [Ca2+]o and high [Na+]o, aNai and DT modifications were similar both in adult and senescent papillary muscles. During high [Ca2+]o, aNai decreased to a similar extent in both adult and senescent papillary muscles, while DT increased by 37.8% in adult and by 67.8% in senescent (p < .05 vs adult). Simultaneous reduction of [Na+]o and [Ca2+]o decreased aNai from 8.1 +/- 1.2 to 6.8 +/- 1.1 mM in adult (-1.3 mM), and from 8.4 +/- 1.0 to 7.2 +/- 1.0 mM in senescent (-1.2 mM) papillary muscles while DT decreased by 22.1% in adult and by only 12.0% in senescent (p < .01 vs adult) papillary muscles. Simultaneous increase of [Na+]o and [Ca2+]o similarly increased aNai in both adult senescent papillary muscles, but decreased DT by 28.5% in adult and by 11.7% in senescent (p < .01 vs adult). After [Na+]o modifications, the equilibration time for the ratio of external and internal sodium ion activities was slowed in senescent papillary muscles (i.e., in low [Na+]o solution the equilibration time was 4.6 +/- 0.9 min in adult and 6.3 +/- 1.2 min in senescent papillary muscles, p < .001). CONCLUSIONS: Similar changes of aNai during transmembrane Na+ and Ca2+ gradients modifications associated to changes in contractile force seem to demonstrate that Na(+)-Ca2+ exchange is probably not modified by the aging process. However, the slow equilibration time for the ratio of Na+ activities might reflect an age-related reduction of the Na(+)-K+ pump activity.

Action Potentials↗
PubMed1996

[LDL oxidation in homozygous familial hypercholesterolemia: effects of selective LDL-apheresis treatment].

Homozygous familial hypercholesterolemia (HFH) results from a mutation affecting both the structure and function of a cell surface receptor that removes low density lipoproteins (LDL) from plasma. The disorder is characterized by autosomal dominant inheritance, a lifelong elevation in the concentration of LDL-bound cholesterol in blood and by cholesterol deposits that form xanthomas and early coronary artery disease. HFH patients, as a result of the increased levels and prolonged residence time of LDL in plasma, have a strong tendency toward accumulation of LDL-cholesterol in the arterial wall causing premature atherosclerosis. Selective LDL-apheresis (LA) on dextran/sulphate cellulose columns is the best therapy reducing mortality of these patients. We previously showed that prolonged lifelong enhanced LDL oxidation in HFH. LDL undergo oxidation before being taken up by macrophages then transformed into foam cells. At the present time, the relevance of the in vitro macrophages studies to the accumulation of cholesterol esters in scavenger cells of HFH patients is not yet established. The aim of this study was to investigate LDL oxidation, induced by xanthine (2 mM)+xanthine oxidase (100 mU), and cholesterol esterification in macrophages, in 8 HFH patients before and after LA. LDL peroxidation by conjugated-diene absorbance showed an increased resistance against oxidation after LA: lag time 129 +/- 25 vs 112 +/- 27 min, p < 0.05; diene production 9.1 +/- 2.1 vs 13.9 +/- 2.5 nM/min/mg LDL, p < 0.01. Peroxidation was also evaluated from lipid peroxides (158 +/- 34 vs 57 +/- 18 nM/mg protein after LA, p < 0.05) and malonyldialdehyde (38 +/- 12 vs 27 +/- 8 nM/mg protein after LA, p < 0.05) content. When oxidized LDL was run on polyacrylamide gel extensive apo-B100 fragmentation was observed in LDL before LA, vs a less fragmentation after LA. A similar reduction was obtained in LDL agarose mobility after LA (1.7 +/- 0.2 vs 2.5 +/- 0.2, p < 0.05). Cholesterol esterification in mouse peritoneal macrophages was also decreased after LA (8.5 +/- 1.8 vs 14.6 +/- 2.7 nM/mg cell protein/12 hours, p < 0.05). Vitamin E content of LDL (mg/g protein) was increased after LA (4.44 +/- 1.0 vs 3.9 +/- 1.2, p < 0.05). Thus, selective LA, not only decreases the pool of LDL, but it also induces changes that render LDL less susceptible to oxidation and decreased high cholesterol esterification in macrophages. The prevention of these mechanisms by LA contributes actively to retard atherogenesis in HFH patients.

Analysis of Variance↗
PubMed1995

Oxidative structural modifications of low density lipoprotein in homozygous familial hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia (FH), as a result of the increased levels and prolonged residence time of low density lipoprotein (LDL) in plasma, have a strong tendency toward accumulation of LDL-cholesterol in the arterial wall, causing premature atherosclerosis. This phenomenon may enhance per se the physiological degradation of both protein and lipid component of LDL, which be more susceptible to oxidative damage induced by oxygen radicals. It is well known that LDL may undergo oxidative modification before being taken up by macrophages which are then transformed into foam cells. It has been suggested that platelet-activating factor (PAF) may play an important role in atherogenesis and PAF catabolism is known to be mediated by serum acetylhydrolase, an enzyme that is normally associated with LDL. Thus, the present study was designed to investigate the structural properties of LDL, including acetylhydrolase activity, in homozygous FH as compared to normolipidemic subjects before and after xanthine/xanthine oxidase-mediated oxidation. We studied 8 homozygous FH patients matched with 8 normolipidemic volunteers. Lipids of LDL fraction were extracted and verified by thin layer chromatography (TLC) analysis. Fatty acids were methylated and injected into a gas chromatograph/mass spectrometer. Vitamin E in LDL was determined by high performance liquid chromatography (HPLC). As an index of susceptibility of LDL to oxidative modifications, the formation of lipid-conjugated dienes was continuously monitored at 234 nm. Lipid peroxidation was also evaluated from the amount of both lipid peroxides (LPO) and malonyldialdehyde (MDA) content. Apolipoprotein (apo) B-100 on LDL was carried on polyacrylamide and agarose gel electrophoresis. In the homozygous FH patients, the relative content of cholesteryl ester was slightly increased. Interestingly, the relative amount of arachidonic acid (20:4) was constantly increased in each lipid fraction in homozygous FH patients. The amount of vitamin E was not significantly different in the patient group from that in the control group. However, LDL from patients carried lower levels of vitamin E (nmol/mg LDL) than controls (2.7 +/- 0.4 vs. 2.9 +/- 0.3 P = NS). The results shows that lag time (min) was decreased (82 +/- 19 vs. 111 +/- 21; P < 0.05) and the maximal rate of diene production and total diene production was increased in homozygous FH patients. Mean levels of MDA were similar in both groups before oxidation, but levels after initiation of oxidation were significantly higher in the patient group. In contrast, mean levels of LPO were already higher in patients before oxidation (58 vs. 27 nmol/mg of protein; P < 0.05), and after initiation of oxidation were also significantly higher at each time points. When oxidized LDL was run on a polyacrylamide gel, an extensive apo B-100 fragmentation replaced by lower molecular mass fragments ranging from 45,000 to 205,000 m.wt., was observed only in LDL from homozygotes. Relative LDL agarose gel mobility shows that LDL from patients migrated higher than LDL of controls. Finally acetylhydrolase activity associated with LDL in patients was significantly reduced as compared to controls. Thus, in homozygous FH patients, LDL appeared more susceptible to oxidation in vitro; the indices for LDL oxidizability were all significantly different from those of controls. This phenomenon might be due to prolonged residence time of LDL in these patients, as suggested from high basal LPO levels and lower vitamin E levels carried by LDL. This hypothesis may explain together with the high content of arachidonic acid, the enhanced susceptibility of LDL from homozygous FH patients to oxidative damage.

Apolipoprotein B-100↗
PubMed1995

Hyperlipidaemia and atherosclerotic cerebrovascular disease.

Controversies exist concerning the role of hypercholesterolaemia as a risk factor for nonhaemorrhagic stroke because intracranial arteries seem to be more resistant than coronary arteries to cholesterol-induced endothelial damage. Only very high levels of serum cholesterol seem to be a significant risk factor. It is possible that coronary heart disease may occur earlier in life than cerebrovascular atherosclerosis, and it could then become the cause of stroke. In our view, the causal relationship between very low levels of serum cholesterol and haemorrhagic stroke is unlikely, and cholesterol-lowering treatment appears to be safe. New studies should consider the particular metabolic aspects of intracranial arteries and the independent role of lipoprotein (a), apolipoprotein E phenotypes and other molecular and genetic mechanisms involved in atherosclerotic cerebrovascular disease.

Arteriosclerosis↗
PubMed1994

Modification of flower color in florist's chrysanthemum: production of a white-flowering variety through molecular genetics.

Chimeric chalcone synthase (CHS) constructs were prepared in both anti-sense and sense orientations, and introduced into the chrysanthemum cultivar Moneymaker, along with a T-DNA vector lacking a CHS construct. For both the anti-sense and sense constructs, the majority of the plants produced pink flowers typical of Moneymaker itself. Of 133 sense and 83 anti-sense transgenic individuals 3 of each set produced fully white or very pale pink flowers. No white-flowering transgenic plants were obtained in control transformations. The white flowers were found to accumulate higher levels of chalcone synthase precursors and to have reduced levels of chalcone synthase message. A small-scale field trial was performed to evaluate the stability of the phenotype throughout a series of vegetative propagation steps and during plant growth. The white-flowering trait was maintained well through vegetative propagation; however, during growth of individual white-flowering plants, some pink color was found in some flowers. At one site 2% of the white-flowering plants produced a few pink flowers; at two other sites, as many as 10-12% of the plants produced pale pink flowers.

Acyltransferases↗
PubMed1994

Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme that catabolizes platelet-activating factor.

Platelet-activating factor (PAF) can exert profound inflammatory effects at very low concentrations. In plasma, PAF is hydrolyzed to lyso-PAF by acetylhydrolase, an enzyme that circulates bound to LDL. Previous studies suggest that oxygen radicals may act synergistically with PAF to potentiate tissue injury. However, mechanisms underlying this interaction have not been elucidated. In this study we investigated whether oxygen radicals may inactivate PAF acetylhydrolase. PAF acetylhydrolase activity was measured in human plasma and purified LDL before and after exposure to radicals (10-20 nmol/min per ml) generated by xanthine/xanthine oxidase. Oxygen radicals induced > 50% loss of PAF acetylhydrolase activity within 60 s and almost complete inactivation by 10 min. This phenomenon was irreversible and independent of oxidative modification of LDL. Inactivation occurred without changes in the affinity constant of the enzyme (Km was 17.9 microM under control conditions and 15.1 microM after exposure to oxygen radicals). Inactivation was prevented by the scavengers superoxide dismutase or dimethylthiourea or by the iron chelator deferoxamine. Thus, superoxide-mediated, iron-catalyzed formation of hydroxyl radicals can rapidly and irreversibly inactivate PAF acetylhydrolase. Since concomitant production of PAF and oxygen radicals can occur in various forms of tissue injury, inactivation of acetylhydrolase might represent one mechanism by which oxygen radicals may potentiate and prolong the proinflammatory effects of PAF.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗