Biomedical subjects

Marina Camera

Publications and source records attributed to Marina Camera.

7 recordsLinked to original sources

PubMed2003

Platelet activation induces cell-surface immunoreactive tissue factor expression, which is modulated differently by antiplatelet drugs.

OBJECTIVE: Tissue factor (TF) is the main activator of the coagulation cascade occurring in physiologic and pathologic conditions. Recent data suggest that human platelets might contain TF that is possibly derived from leukocytes. In this study, we investigated whether intraplatelet TF can be exposed on the membrane by platelet agonists. The modulation of this process by antiplatelet drugs has been evaluated as well. METHODS AND RESULTS: Flow cytometric analysis of unstimulated platelets showed a small amount of membrane-associated immunoreactive TF (irTF) in whole blood, platelet-rich plasma, and washed platelets isolated from healthy subjects. ADP, thrombin receptor-activating peptide, and epinephrine significantly increased functionally active, membrane-associated irTF. ADP induced irTF exposure in a concentration- and time-dependent fashion. Agonist-induced irTF expression was completely inhibited by iloprost but not by aspirin. Interestingly, glycoprotein IIb/IIIa antagonists did not inhibit but rather potentiated the stimulatory effect of ADP on platelet irTF expression. Real-time polymerase chain reaction experiments showed detectable amounts of TF mRNA in unstimulated platelets. CONCLUSIONS: These findings indicate that platelet agonists and antiplatelet drugs might modulate platelet-associated irTF expression. Regulated TF expression establishes the potential for a previously unrecognized role for platelets in sustaining thrombus formation and growth via coagulation-mediated mechanisms.

Antigens, Surface↗

PubMed2003

Statins in coronary bypass surgery: rationale and clinical use.

Statin therapy prevents the first occurrence and recurrence of coronary events and reduces cardiovascular and general mortality in patients with coronary artery disease. These compounds modulate a variety of processes involved in the pathophysiology of arteriosclerosis and vascular graft disease by lipid-dependent and lipid-independent (pleiotropic) mechanisms. As a result, statins produce angiographic and clinical benefits in patients undergoing coronary bypass surgery. We review the present knowledge about the effects of statins on this pathologic condition and the evidence supporting an early treatment initiation.

Arteriosclerosis↗

PubMed2003

Vascular thrombogenicity induced by progressive LDL oxidation: protection by antioxidants.

Oxidative modification of LDL, which dysregulates the homeostasis between blood and vascular cells, and alterations of endothelial function are considered among the early events in the pathogenesis of atherosclerosis. This study was designed to evaluate the impact of progressive LDL oxidation on the thrombotic response both in vitro and in vivo, and to address the potential effect of antioxidants. Tissue factor was induced by progressive LDL oxidation in HUVEC, and this event was in parallel to the appearance of the apoptotic phenotype. Both these phenomena were mediated by ERK1/2 activation and were prevented by LDL pre-enrichment with antioxidants. In contrast, antioxidants failed to affect tPA and PAI-1 secretion, which was increased by LDL, either native or oxidized. Tissue factor-pathway inhibitor was also increased upon HUVEC exposure to progressively oxidized LDL. LDL, in the presence of an oxidative agent, trigger a thrombogenic response in vivo, mostly TF-dependent, in an in situ model of platelet deposition. This effect was markedly attenuated when LDL were enriched with antioxidants. It can be concluded that vascular thrombogenicity is induced by progressive LDL oxidation and that alterations of the antioxidant/oxidant balance of the LDL particle in favor of the antioxidant tone are protective against the thrombotic response triggered by oxidative stress. The extrapolation of these data in a clinical setting, even if not easy, offers potential insights for the use of antioxidants in the prevention of thrombotic complications associated with atherothrombosis.

Antioxidants↗

PubMed2002

Oxidized phospholipids inhibit cyclooxygenase-2 in human macrophages via nuclear factor-kappaB/IkappaB- and ERK2-dependent mechanisms.

OBJECTIVE: Oxidized low-density lipoproteins (ox-LDL) or their components suppress macrophage inflammatory response by down-regulating cytokine synthesis, nitric oxide synthase and inducible cyclooxygenase (Cox-2). This event is crucial for the pathophysiological process leading to the formation of atherosclerotic plaque. Our present study focused on the mechanisms through which oxidized phospholipids inhibit LPS-induced Cox-2 expression in human macrophages. METHODS: Macrophages were incubated with a mixture of oxidized fragmented phospholipids (ox-PAPC), present in modified LDL, and then exposed to LPS. Cox-2 was evaluated in terms of protein levels, mRNA and activity. RESULTS: Ox-PAPC dose-dependently inhibited Cox-2 protein, mRNA and activity by preventing NF-kappaB binding to DNA. This effect was consequent to alterations of the degradation pattern of IkappaBalpha. Moreover, ox-PAPC markedly prevented extracellular signal-regulated kinase (ERK2) activation, leading to Cox-2 expression, whereas activation of the transcription factor peroxisome proliferator-activated receptors (PPARs) was not influenced. CONCLUSION: ox-PAPC down-regulates LPS-induced Cox-2 expression in human macrophages by targeting both NF-kappaB/IkappaB and ERK2 pathways. An altered inflammatory response by macrophages within atheromata may contribute to the progression of atherosclerosis.

Cell Culture Techniques↗

PubMed2002

Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering.

The expression of tissue factor (TF), mainly by infiltrated inflammatory cells, has been shown to be responsible for the thrombogenicity associated with atheroma. The contribution of the nonlipid-related effects of statins to the clinical benefits of statin therapy is currently under intense investigation. In this study, we evaluated the ability of fluvastatin to modulate TF expression and macrophage accumulation in rabbit carotid intimal lesions independently of cholesterol lowering. Male rabbits were fed for 30 days a 1% cholesterol-rich diet with or without fluvastatin at 5 mg/kg per day. Two weeks from the start of treatment, a silastic collar was placed around the carotid artery. Fifteen days later, the animals were killed, and carotid segments were excised and processed. The atherogenic diet caused a consistent increase in plasma cholesterol levels (610+/-231 mg/dL versus 50+/-9 mg/dL at baseline), which were not affected by fluvastatin (603+/-248 mg/dL). In the rabbits fed a high cholesterol diet without fluvastatin, an intimal lesion with macrophage accumulation and TF expression was detected. Fluvastatin significantly reduced TF and macrophage content of the lesion (-50% for both). Results indicate that fluvastatin may attenuate the inflammatory and thrombogenic potential of atherosclerotic lesions through a mechanism(s) other than cholesterol reduction, providing new insight regarding the complex mode of action of statins.

Animals↗

PubMed2002

Cholesterol-induced thrombogenicity of the vessel wall: inhibitory effect of fluvastatin.

High cholesterol levels are a known risk factor for coronary events. The molecular links between high serum cholesterol and the increased thrombogenicity of the arterial wall are still matter of investigation. In the present study we investigate the relationship between plasma cholesterol, thrombus formation and TF expression in a atherosclerotic rabbit model. Hypercholesterolemic rabbits showed a pronounced TF staining as well as NF-kappaB activation in the aortic arch. A consistent vessel wall platelet deposition was also observed. Treatment with fluvastatin reduced lipid accumulation, TF overexpression (-60%), NF-kappaB activation, and platelet deposition (-56%). In vitro studies showed that the drug upregulated IkappaB alpha in unstimulated as well as in TNFalpha-stimulated cells and also impaired the TNFalpha-induced Cdc42 prenylation, indicating that fluvastatin interferes with the transcriptional activation of TF gene. These results indicate that the prothrombotic phenotype of arterial wall, associated with elevated serum cholesterol levels, is mediated by TF overexpression. Fluvastatin treatment reduces the prothrombotic tendency by inhibiting TF synthesis.

Animals↗

PubMed2002

Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study.

Statins appear to have beneficial effects on fibrous cap stabilisation but their effects on plaque thrombogenicity have not been reported. To evaluate the thrombogenicity of human carotid plaques before and after atorvastatin treatment, 59 patients with bilateral carotid stenosis eligible for two-step carotid endoarterectomy (CEA) were randomly assigned to atorvastatin, 20 mg/day, or placebo. Histological and immunohistochemical analyses, Tissue Factor (TF), Tissue Factor Pathway Inhibitor (TFPI) antigens (Ag) and TF activity were determined in endoarterectomy specimens obtained at baseline and after treatment. Mean TFAg and TFPIAg levels from plaques removed at the first CEA were 55 +/- 56 and 32 +/- 26 pg/mg. After placebo, TFAg and TFPIAg content was higher in the second than the first CEA. Plaques removed at the second CEA from atorvastatin-treated patients had a lower macrophage content than plaques at the first CEA. TFAg and TFPIAg levels, and TF activity in plaques after atorvastatin treatment were lower (respectively 29, 18% and 56%) than after placebo. These findings indicate that atorvastatin reduce the inflammatory/thrombotic phenotype of carotid plaque, suggesting that these drugs may indeed have a beneficial effect on cerebrovascular events.

Aged↗