Biomedical subjects

Lavinia Forte

Publications and source records attributed to Lavinia Forte.

6 recordsLinked to original sources

PubMed2006

Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism.

BACKGROUND: Recent studies indicate that T-cell activation may play an important role in the pathophysiology of acute coronary syndromes (ACS). However, although those studies detected T-cell expansion in peripheral blood cells, demonstration of specific T-cell expansion within the plaque of patients with ACS is lacking. The present study aims to address whether a specific, immune-driven T-lymphocyte recruitment occurs within the unstable plaque of patients with ACS. METHODS AND RESULTS: We simultaneously examined the T-cell repertoire using CDR3 size analysis both in coronary plaques (obtained by directional atherectomy) and in peripheral blood of patients with either ACS (n=11) or chronic stable angina (n=10). Unstable plaques showed a 10-fold increase in T-cell content by quantitative PCR. Using spectratyping analysis, we found several specific T-cell clonotype expansions only in unstable plaque from each patient with ACS, indicating a specific, antigen-driven recruitment of T cells within unstable lesions. CONCLUSIONS: For the first time, T-cell repertoire was investigated directly into coronary plaques; using this approach, we demonstrate that coronary plaque instability in the setting of ACS is associated with immune-driven T-cell recruitment, specifically within the plaque.

Acute Disease↗

PubMed2005

C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation.

OBJECTIVE: Inflammation plays a pivotal role in atherothrombosis. In addition to being a prognostic marker for major cardiovascular events, recent data indicate that C-reactive protein (CRP) might directly promote atherothrombosis by exerting direct effects on vascular cells. The aim of the present study was to determine whether CRP might affect the prothrombotic and proliferative characteristics of endothelial (ECs) and smooth muscle cells (SMCs). METHODS AND RESULTS: Incubation of ECs and SMCs with CRP resulted in a dose-dependent activation of cell proliferation, which was mediated by activation of the p44/42 MAP Kinase (ERK 1/2) pathway. In addition, CRP also induced tissue factor (TF) expression in both cell types in a dose-dependent fashion, exerting its effect at the transcriptional level, as demonstrated by semiquantitative and by real time PCR. Activation of the transcription factor, NF-kappaB, by CRP was demonstrated by EMSA and by suppression of TF expression by the NF-kappaB inhibitor, pyrrolidine-dithio-carbamate ammonium. CONCLUSIONS: These data indicate that CRP exerts direct effects on ECs and SMCs by promoting proliferation and TF expression and support the notion that CRP, besides representing a marker of inflammation, is an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the vessel wall.

Animals↗

PubMed2004

Tissue factor binding of activated factor VII triggers smooth muscle cell proliferation via extracellular signal-regulated kinase activation.

BACKGROUND: Tissue factor (TF) is the main initiator of coagulation in vivo. Recently, however, a role for TF as a cell receptor involved in signal transduction has been suggested. The aim of the present study was to assess whether activated factor VII (FVIIa) binding to TF could induce smooth muscle cell (SMC) proliferation and to clarify the possible intracellular mechanism(s) responsible for this proliferation. METHODS AND RESULTS: Cell proliferation was induced by FVIIa in a dose-dependent manner, as assessed by [3H]thymidine incorporation and direct cell counting, whereas no response was observed with active site-inhibited FVIIa (FVIIai), which is identical to FVIIa but is devoid of enzymatic activity. Similarly, no proliferation was observed when binding of FVIIa to TF was prevented by the monoclonal anti-TF antibody AP-1. Activation of the p44/42 mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinases 1 and 2 [ERK 1/2]) pathway on binding of FVIIa to TF was demonstrated by transient ERK phosphorylation in Western blots and by suppression of proliferation with the specific MEK (MAP kinase/ERK kinase) inhibitor UO126. ERK phosphorylation was not observed with FVIIai or when cells were pretreated with AP-1. CONCLUSIONS: These data indicate a specific effect by which binding of FVIIa to TF on the surface of SMCs induces proliferation via a coagulation-independent mechanism and possibly indicate a new link between coagulation, inflammation, and atherosclerosis.

Animals↗

PubMed2004

Inhibition of the tissue factor coagulation pathway.

It is widely accepted that blood coagulation in vivo is initiated during normal hemostasis, as well as during intravascular thrombus formation, when the cell-surface protein, tissue factor, is exposed to the blood as a consequence of vascular injury. In addition to its essential role in hemostasis, tissue factor may be also implicated in several pathophysiological processes, such as intracellular signaling, cell proliferation, and inflammation. For these reasons, the tissue factor:factor VIIa complex has been the subject of intense research focus. Many experimental studies have demonstrated that inhibition of tissue factor:factor VIIa procoagulant activity are powerful inhibitors of in vivo thrombosis and that this approach usually results in less pronounced bleeding tendency, as compared to other "more classical" antithrombotic interventions. Alternative approaches may be represented by transfecting the arterial wall with natural inhibitors of tissue factor:factor VIIa complex, such as tissue factor pathway inhibitor, which may result in complete inhibition of local thrombosis without incurring in potentially harmful systemic effects. Additional studies are warranted to determine the efficacy and safety of such approaches in patients.

Animals↗

PubMed2003

Activated platelets stimulate tissue factor expression in smooth muscle cells.

UNLABELLED: Tissue factor (TF)-induced activation of the coagulation plays a key role in the pathophysiology of acute coronary syndromes. Because TF represents the initial trigger of the coagulation cascade, its expression in the arterial wall is tightly regulated. OBJECTIVE: To determine whether and which soluble mediators released during platelet activation may upregulate TF expression in smooth muscle cells (SMCs). METHODS AND RESULTS: Rabbit SMCs were challenged with collagen-activated platelets and their effects on TF mRNA transcription and protein expression were evaluated at different time points (30 min, 1, 2, 4, 8, 12 and 24 h) by RT-PCR, immunofluorescence and a two-stage colorimetric assay. A progressive increase in TF mRNA, peaking at 2 h, was evident in SMCs stimulated with activated platelets with respect to baseline. The increase in TF mRNA expression was associated with a parallel increase in TF protein, as demonstrated by immunofluorescence and by colorimetric assay. In a different set of experiments, selected platelet-derived soluble mediators were shown to induce TF mRNA expression. CONCLUSIONS: Activated platelets upregulate TF, via release of several soluble mediators, in a cell population widely expressed in the vessel wall and in atherosclerotic plaques, such as SMCs. This phenomenon might play an important role in sustaining thrombus formation in vivo.

Animals↗

PubMed2002

Role of tissue factor pathway inhibitor in the regulation of tissue factor-dependent blood coagulation.

Tissue factor pathway inhibitor (TFPI) is a multivalent, Kunitz-type plasma proteinase inhibitor that modulates tissue factor-dependent coagulation in vivo. TFPI possesses a peculiar two-step mechanism of action; it directly inhibits activated factor X and subsequently produces feedback inhibition of the factor VIIa/tissue factor catalytic complex in a factor Xa-dependent fashion. TFPI biochemistry and physiology have been extensively studied during the last decade. Its pathophysiologic role in thrombotic disorders has, however, only recently started to be unraveled. In particular, circulating plasma TFPI levels have been found to modulate the activity of the tissue factor-dependent coagulation cascade. In animal models, neutralization of circulating TFPI activity results in restoration of intravascular thrombus formation previously abolished by aspirin. In patients with acute myocardial infarction, TFPI plasma levels measured in blood samples obtained from the coronary sinus were significantly lower than those measured in blood obtained from the ascending aorta, indicating acute consumption of TFPI within the coronary circulation of patients with intracoronary thrombosis. Finally, recent data indicate that transfection of the arterial wall with the gene coding for TFPI is an effective therapeutic intervention to prevent intravascular thrombus formation. Taken together, these observations underline the pathophysiologic importance of TFPI in regulating the procoagulant activity of tissue factor and open new potential therapeutic approaches for the treatment of thrombotic disorders.

Amino Acid Sequence↗