Hyperlipidemias: Davì G

Santilli F, Basili S, Ferroni P, Davì G. · Center of Excellence on Aging, University of Chieti "G. D'Annunzio" School of Medicine, Via Colle dell'Ara, I-66013, Chieti, Italy. · Intern Emerg Med. · Pubmed #18043876 No free full text.

Abstract: Several distinct lines of investigation in the context of atherosclerosis dealing with low-grade inflammation, oxidative stress and platelet activation are now emerging, with CD40/CD40L system as the missing link. CD40 ligand is a transmembrane glycoprotein structurally related to tumour necrosis factor-alpha and more than 95% of the circulating CD40L derives from platelets. CD40L appears as a multiplayer of several cell types in the inflammatory network. The peculiarity of CD40L as an inflammatory mediator derived from platelets expands the functional repertoire of platelets from players of haemostasis and thrombosis to powerful amplifiers of inflammation by promoting the release of cytokines and chemokines, cell activation and cell-cell interactions. The multifunctional role of CD40L, as a simultaneous activator of all these systems, further blurs the intricate relationship between such events both in the physiological systems and the pathological derangement occurring in atherothrombosis.

Ferroni P, Basili S, Santilli F, Davì G. · Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Rome, Italy. · Pathophysiol Haemost Thromb. · Pubmed #16877882 No free full text.

Abstract: Elevated low-density lipoprotein (LDL) cholesterol (LDL-C) levels represent one of the most important risk factors for atherosclerosis and therefore cardiovascular morbidity and mortality. LDL-C operates at different levels and through various classic and non-classic mechanisms. In particular, increased or modified LDL enhances platelet function and increases sensitivity of platelets to several naturally occurring agonists. Agents that lower LDL-C in hypercholesterolemic patients have been shown to interfere with platelet function. Several studies, in fact, suggested that statins exert anti-thrombotic effects largely as a result of an anti-platelet activity. Among the other LDL-C-lowering agents those acting by interfering with cholesterol reabsorption from the gut (cholestyramine, colestipol) do not appear to interfere with platelet function, whereas peroxisome proliferator-activated receptor agonists (such as fibrates) can inhibit platelet function. The full potential of these drugs in vascular protection is only just being realized. Further studies are still needed to elucidate the full therapeutic benefits of these agents in plaque stabilization and thrombosis.

Davì G, Falco A. · Center of Excellence on Aging, G d'Annunzio Foundation, University of Chieti, G d'Annunzio School of Medicine, Chieti, Italy. · Lupus. · Pubmed #16218483 No free full text.

Abstract: Low-grade inflammation, enhanced oxidant stress and lipid peroxidation have been shown in association with increased cardiovascular risk associated with cardiovascular events. It has been hypothesized that the low-grade inflammatory state characterizing metabolic disorders such as obesity, hypercholesterolemia, type 2 diabetes mellitus and homozygous homocystinuria may be the primary trigger of thromboxane-dependent platelet activation mediated, at least in part, through enhanced lipid peroxidation. Interestingly, as the clinical course of systemic lupus erythematosus (SLE), in particular in the presence of antiphospholipid antibodies, may be complicated by vascular disease, several mechanisms contributing to vascular complications have been documented also in this setting, including enhanced lipid peroxidation and thromboxane biosynthesis. Although epidemiological studies show an inverse relationship between antioxidant vitamin intake and cardiovascular disease, several clinical trials have obtained conflicting results on the effects of vitamin E on the risk of cardiovascular events. The availability of analytical tools for measuring F2-isoprostane biosynthesis in man has improved our understanding of the interplay between lipid peroxidation and low-grade inflammation. The use of F2-isoprostane as a biochemical end-point for dose-finding studies may allow reassessing the adequacy of vitamin supplementation in different clinical settings.

Ferroni P, Basili S, Falco A, Davì G. · Department of Experimental Medicine and Pathology, University La Sapienza, 00161 Rome, Italy. · Antioxid Redox Signal. · Pubmed #15242556 No free full text.

Abstract: Hypercholesterolemia is the dominant risk factor associated with atherothrombotic disorders in the western world. Consequently, much attention has been devoted to defining its role in the pathogenesis of atherosclerosis. It is currently recognized that hypercholesterolemia induces phenotypic changes in the microcirculation that are consistent with oxidative and nitrosative stresses. Superoxide is generated via several cellular systems and, once formed, participates in a number of reactions, yielding various free radicals, such as hydrogen peroxide, peroxynitrite, or oxidized low-density lipoproteins. Once oxidant stress is invoked, characteristic pathophysiologic features ensue, such as platelet activation and lipid peroxidation, which are both involved in the initiation and progression of the atherosclerotic lesions. Thus, therapeutic strategies that act to maintain the normal balance in the oxidant status of the vascular bed may prove effective in reducing the deleterious consequences of hypercholesterolemia.

Ferroni P, Basili S, Davì G. · Dipartimento di Medicina Sperimentale e Patologia, Università La Sapienza, Roma. · Recenti Prog Med. · Pubmed #15143955 No free full text.

Abstract: Hypercholesterolemia and overt atherosclerotic disorders have been associated with a low-grade inflammation that involves not only the intrinsic cells of the artery wall, but also circulating cells. Platelets as well as monocytes participate importantly in this disease process through the release of a wide variety of biologically active substances. Recent findings on the inflammatory actions of platelets have opened new perspectives in the comprehension of the pathogenetic mechanism(s) of atherosclerosis. Stimulated platelets, in fact, actively synthesize proinflammatory cytokines which have been all involved in the inflammatory process associated to hypercholesterolemia and plaque development. In this context, increasing evidence suggests that interrelated inhibition of inflammation and thrombosis induced by statins could largely contribute to clinical benefits from lipid-lowering therapy.

Di Febbo C, Porreca E, Bucciarelli T, Milani M, Davì G. · No affiliation provided · Thromb Haemost. · Pubmed #12152665 No free full text.

This publication has no abstract.

Cipollone F, Mezzetti A, Porreca E, Di Febbo C, Nutini M, Fazia M, Falco A, Cuccurullo F, Davì G. · Center of Excellence on Aging, University of Chieti G. D'Annunzio School of Medicine, Chieti, Italy. · Circulation. · Pubmed #12135935 links to  free full text

Abstract: BACKGROUND: Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins. METHODS AND RESULTS: We studied 80 hypercholesterolemic patients and 80 matched healthy subjects. Hypercholesterolemic subjects had enhanced levels of sCD40L, factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) compared with healthy subjects. sCD40L correlated with total cholesterol and LDL cholesterol. Moreover, sCD40L was positively associated with in vivo platelet activation, as reflected by plasma P-selectin and urinary 11-dehydro-thromboxane B2, and with procoagulant state, as reflected by FVIIa and F1+2. Inhibition of cholesterol biosynthesis by pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, FVIIa, and F1+2. CONCLUSIONS: This study suggests that sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state and demonstrates that statin therapy may significantly reduce sCD40L and the prothrombotic state.

Romano M, Mezzetti A, Marulli C, Ciabattoni G, Febo F, Di Ienno S, Roccaforte S, Vigneri S, Nubile G, Milani M, Davì G. · Institute of Medical Pathology and Mediterranean Medicine, University of Messina, Italy. · J Investig Med. · Pubmed #10822898 No free full text.

Abstract: BACKGROUND: Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase inhibitors reduces the incidence of atherosclerosis-related cardiovascular events. Adhesion molecules, regulating interactions between vascular and circulating cells, may play a central role in the pathogenesis of atherosclerosis and related complications. In the present report we examined the impact of the HMG-CoA reductase inhibitor fluvastatin on plasma levels of P-selectin and ICAM-1. METHODS: Plasma levels of P-selectin and ICAM-1 were determined using an enzyme immunoassay in 26 patients with type IIa hypercholesterolemia randomized to treatment with either fluvastatin (80 mg/d) or placebo in a double blind fashion for 12 weeks. RESULTS: Fluvastatin administration reduced either P-selectin (118 +/- 63 vs 81 +/- 36 ng/mL [-31%], P = 0.0015) or ICAM-1 (264 +/- 75 vs 228 +/- 68 ng/mL [-13.7%], P = 0.0033) levels. Fluvastatin also lowered urinary 11-dehydro-TXB2 (1396 +/- 536 vs 1009 +/- 378 pg/mg creatinine [-27%], P = 0.0015) and von Willebrand Factor levels (1456 +/- 716 vs 1203 +/- 527 U/L [-17.4%], P = 0.0275), and a direct correlation was observed between P-selectin and 11-dehydro-TXB2 levels (r = 0.588, P = 0.0033). Patients treated with fluvastatin displayed an increase in nitric oxide (NO) generation, evaluated with measurements of serum NO2-/NO3-, (4.7 +/- 1 vs 8.9 +/- 3.1) mumol/L [98%], P = 0.0046). Moreover, an inverse correlation was observed between NO2-/NO3- and P-selectin (r = -0.420; P = 0.0343), 11-dehydro-TXB2 (r = -0.511; P = 0.0106), or LDL (r = -0.742; P = 0.0002) levels. CONCLUSIONS: These results may provide novel biochemical basis for the beneficial clinical effects of HMG-CoA reductase inhibitors in hypercholesterolemia.

Santilli F, Bucciarelli L, Noto D, Cefalù AB, Davì V, Ferrante E, Pettinella C, Averna MR, Ciabattoni G, Davì G. · Center of Excellence on Aging, Department of Medicine, and Department of Drug Sciences, University of Chieti G. d'Annunzio Schools of Medicine and Pharmacy, 66013 Chieti, Italy. · Free Radic Biol Med. · Pubmed #17893038 No free full text.

Abstract: The receptor for advanced glycation endproducts (RAGE) is overexpressed at sites of vascular pathology. A soluble RAGE isoform (sRAGE) neutralizes the ligand-mediated damage by acting as a decoy. We hypothesized that in hypercholesterolemia up-regulation of the ligand-RAGE axis may bridge impairment of nitric oxide biosynthesis with oxidative stress. We measured in 60 hypercholesterolemic patients and 20 controls plasma total sRAGE levels, urinary 8-iso-prostaglandin (PG) F(2alpha) excretion, and plasma levels of asymmetric dimethylarginine (ADMA). The effects of two structurally different statins (pravastatin and atorvastatin) on these parameters were analyzed in 20 hypercholesterolemic subjects free of vascular disease. Plasma sRAGE was significantly lower, ADMA and urinary 8-iso-PGF(2alpha) were higher, in hypercholesterolemic versus normocholesterolemic patients. Patients on statin treatment with previous myocardial infarction had lower 8-iso-PGF(2alpha), higher sRAGE, and unchanged ADMA levels compared to subjects free of vascular disease. On multivariate regression analysis only 8-iso-PGF(2alpha) and ADMA predicted sRAGE levels. An 8-week treatment with either statin was associated with a significant reduction in urinary 8-iso-PGF(2alpha), whereas only atorvastatin raised sRAGE levels near to normal values, with no change in ADMA levels. sRAGE might serve as an endogenous protecting factor for accelerated atherosclerosis mediated by oxidative stress and endothelial dysfunction in hypercholesterolemia.