Biomedical subjects

L Badimon

Publications and source records attributed to L Badimon.

At least 55 records · Page 3Linked to original sources

PubMed1999

Elevated levels of plasmin-alpha2 antiplasmin complexes in unstable angina.

The evidence of elevated levels of several biochemical markers of prothrombotic state in patients with unstable angina suggests that thrombus formation and lysis play a pivotal role in acute coronary syndromes. The clinical syndrome of unstable angina encompasses a variety of clinical presentations of transient episodes of myocardial ischemia. This study was designed to assess plasmin generation in different settings of unstable angina. Evidence of plasmin generation in patients with unstable angina was measured by circulating plasmin-alpha2 antiplasmin complexes (PAP). A second objective was to identify whether PAP levels had a prognostic value to predict outcome. Eighty-five patients admitted to the coronary care unit for unstable angina were classified into three groups. Group A included 26 patients with postinfarction angina; group B comprised 26 patients with new onset angina; and group C included 33 patients with crescendo angina. Mean PAP levels were higher in the three groups compared to healthy controls. A significant correlation was found between levels of PAP and D-dimer, particularly in postinfarction angina (r = 0.6; p <0.0005). This trial adds new insights into the pathophysiology of unstable angina. It demonstrates that plasmin is generated in the different settings of unstable angina but particularly in postinfarction angina patients where a fibrin-rich thrombus is responsible of the symptoms. However, in this series PAP levels do not predict an uneventful outcome neither in the acute phase nor at long term (6 months).

Aged↗

PubMed1999

A sudden increase in plasma epinephrine levels transiently enhances platelet deposition on severely damaged arterial wall--studies in a porcine model.

Epidemiologic evidence has shown that sympathoadrenal activation plays a triggering role in the onset of acute coronary syndromes. However, its mechanism is not yet clearly understood. The aim of this study was to assess the effect of a sudden increase in epinephrine on platelet deposition on severely damaged vessel wall at shear rate conditions modelling stenotic vessels in the porcine model. The selected epinephrine concentrations (0.5 micromol/l-1 mmol/l) alone or in combination with collagen or ADP did not affect platelet aggregation in vitro either in whole blood or in PRP, although porcine platelets express alpha2-adrenergic receptors as assessed by PCR. In vitro and ex vivo perfusion experiments were performed using the Badimon chamber at high shear rate conditions (1690 s(-1)). In vitro, epinephrine (130 nmol/l) increased platelet deposition on severely damaged vessel wall (exposing tunica media; approximately 1.6-fold, p <0.05) or immobilized collagen (2.2-fold, p <0.01). Ex vivo perfusion experiments were performed from animals that received intravenous epinephrine infusion for one hour at a low (0.3 microg/kg/min; approximately 17 nmol/l in plasma, at 20 min of the infusion) and a high dose (1.0 microg/kg/min; approximately 106 nmol/l in plasma, at 20 min of the infusion). Only the low dose temporarily increased platelet deposition on severely damaged vessel wall during the first 30 min of infusion [2.4-fold (p <0.05) and 4.2-fold (p <0.01) at 10 and 30 min of the infusion respectively] declining afterwards. Thus, in flow conditions typical of atherosclerotic arteries, a sudden physiological release of epinephrine can temporarily enhance platelet deposition on severely damaged vessel wall while an extensive exposure leads to refractoriness.

Animals↗

PubMed1998

Atherogenic concentrations of native low-density lipoproteins down-regulate nitric-oxide-synthase mRNA and protein levels in endothelial cells.

The nitric oxide synthase family of proteins is the unique class of mammalian enzymes that metabolizes L-arginine to form nitric oxide (NO). The atherogenic action of low-density lipoproteins (LDL) may be mediated, in part, by its effects on endothelial-derived nitric oxide. To determine whether native LDL (nLDL), at atherogenic concentrations, are capable of modulating NO synthase expression, we treated human umbilical vein endothelial cells with increasing concentrations of human nLDL (0-240 mg cholesterol/dl) for various time periods (2-48 h). Northern and western blot analyses indicate that both endothelial NO-synthase mRNA and protein are down-regulated by atherogenic concentrations of nLDL (180 and 240 mg cholesterol/dl) after 48 h of incubation. Cycloheximide and actinomycin D experiments suggest that this down-regulation operates at a transcriptional level. Additionally, treatment of the cells with high-density lipoproteins, at human physiological concentrations (45 mg cholesterol/dl), does not appear to alter the expression of endothelial NO synthase which seems to indicate that nLDL affect the gene transcription rate by a specific and concentration-dependent mechanism. These findings may have important implications because they provide a novel mechanism by which hypercholesterolemia induces early changes on endothelial cells that could have pathophysiological significance in the atherosclerotic process.

Arteriosclerosis↗

PubMed1998

Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with heparin and aspirin.

BACKGROUND: The presence of residual mural thrombus may predispose to recurrent thrombotic events in acute coronary syndromes. The purpose of this study was to evaluate the effects of antithrombotic and antiplatelet agents on a preformed, fresh mural thrombus during growth of thrombus. METHODS AND RESULTS: A fresh mural thrombus was formed by perfusing severely injured arterial wall with porcine blood for 5 minutes at a shear rate of 1690 s(-1). Thrombus formation was measured by morphometric analysis (mm2/mm). The average size of a mural thrombus formed in 5 minutes was 0.14+/-0.03 mm2/mm. Progression of thrombus growth within 10 minutes triggered by the preformed thrombus was evaluated in pigs treated with r-hirudin (1 mg/kg per hour i.v.) as a probe for thrombin, high-dose heparin (250 IU/kg per hour i.v.), moderate-dose heparin (100 IU/kg per hour), moderate-dose heparin (100 IU/kg per hour) plus aspirin, aspirin alone (5 mg/kg i.v.), and placebo. Hirudin was associated with a significant decrease (48%) of mural thrombus area and significantly reduced growth of thrombus (0.07+/-0.01), even compared with the highest dose of heparin (0.15+/-0.03), although at lower levels of anticoagulation. Inhibition of growth of thrombus with heparin was dose dependent, showing an inverse correlation of thrombus area with mean plasma heparin concentrations (r=.77, P=.0001). Thrombus size was unchanged by aspirin (0.29+/-0.07) compared with controls (0.28+/-0.07). CONCLUSIONS: Direct inhibition of thrombin activity with r-hirudin completely inhibits growth of thrombus, causes dissolution of a preexisting mural thrombus, and is more effective at lower levels of anticoagulation than the highest dose of heparin at shear rates typical of a moderate coronary stenosis.

Animals↗

PubMed1998

Effects of reducing LDL and increasing HDL with gemfibrozil in experimental coronary lesion development and thrombotic risk.

The use of lipid-lowering drugs has been shown to have beneficial effects in primary and secondary prevention of cardiovascular disease. Gemfibrozil has shown beneficial effects as a lipid lowering agent; however, some proactivating effects on platelet function in vitro have been described. We have studied in a porcine model of atherosclerosis if gemfibrozil could prevent the early vascular effects of a cholesterol-rich diet without inducing platelet activation and, hence, mural thrombosis. Pigs were fed for 50 days with a diet rich in saturated fat and cholesterol (cho). The longitudinal follow-up study showed that in control animals LDL-cho increased significantly up to 181.9 +/- 34.2 mg/dl or 79% of total-cho, while HDL-cho was reduced to 19% of total-cho. Gemfibrozil, at average therapeutic plasma levels (peak levels of 28 micrograms/ml) [corrected], induced a significant reduction in the relative amount of LDL (P < 0.05) and increased HDL (P < 0.05). The increase in fibrinogen plasma levels observed in the control group due to the dietary intervention (+25%) was prevented in the treated animals (-5%). In treated animals, vascular lesions were significantly less severe, platelet deposition upon exposure of damaged vessel wall was unchanged and the fibrin layer deposited on the damaged vessel wall was significantly reduced over control animal values. This short term pharmacologic lipid lowering intervention has been able to slow down lesion development and to reduce fibrin formation onto lesioned disrupted vascular substrates without increasing platelet mural thrombosis.

Animals↗

PubMed1998

Different response to balloon angioplasty of carotid and coronary arteries: effects on acute platelet deposition and intimal thickening.

PTCA is a well-established intervention to reduce the severity of atherosclerotic coronary stenosis. Its primary success rate is seriously handicapped by the high incidence of late restenosis. Given the clinical and social importance of this proliferative process, new strategies are needed to prevent or reduce restenosis. Several animal models as well as different arteries have been used to study neointimal proliferation after arterial injury. A number of agents have shown to reduce neointimal proliferation after arterial injury in the carotids and iliac arteries of rodent models. Unfortunately, these results have not been replicated in humans. We have compared the acute and late response to vascular injury of the carotid and coronary arteries in the pig. Arterial injury was induced by performing balloon angioplasty of the carotid (elastic) and coronary (muscular) arteries in swine. Acute platelet-thrombus formation was evaluated by quantitation of Indium-labeled platelets deposited on the injured segments 1 h after procedure. Measurement of intimal area was performed by morphometry of the most stenotic cross-section at 28 days after balloon angioplasty. Platelet deposition after mild and severe injury in carotids (4 +/- 1 and 56 +/- 13 x 10(6) platelets/cm2, respectively) and coronaries (15 +/- 5 and 141 +/- 20 x 10(6) platelets/cm2, respectively) are significantly greater in deep, than in mild injury (P < 0.005), and significantly greater in coronary than in carotid arteries after deep injury (P < 0.05). Likewise, late neointima formation was significantly greater (P < 0.05) after mild and severe injury in coronary (17 +/- 0.5 and 56 +/- 2%, respectively) than in carotid arteries (5 +/- 0.5 and 12 +/- 1%, respectively). Acute platelet-thrombus formation and late neointimal thickening are modulated by the degree of injury induced during the interventions; and after disruption of the internal elastic lamina, coronary arteries always had significantly more acute thrombus and neointimal thickening. This study emphasizes the importance of the animal species, the type of injury and the artery chosen for studies on restenosis post interventions.

Acute Disease↗

PubMed1998

[Cellular and molecular bases of cholesterol accumulation in the vascular wall and its contribution to the progression of atherosclerotic lesion].

The rupture of atherosclerotic plaques depends mainly on their composition. Vulnerable plaques are those that contain a large lipidic core, which derives either from the retention and modification of LDL and/or from necrosis of foam cells. Most foam cells derive from monocyte/macrophages. Although some of them, especially in advanced plaques, derive from smooth muscle cells. Different receptors involved in the process of foam cell formation have been identified: e.g., scavenger receptors, VLDL receptors and alpha 2-macroglobulin/low density lipoprotein receptor-related proteins. The LDL derived cholesterol collected by these receptors is transformed through the enzyme acyl CoA cholesterol acyl transferase (ACAT) in esterified cholesterol, the hallmark of foam cell formation. High density lipoprotein (HDL) allows the release of free cholesterol from the plasmatic membrane inducing the regression of atherosclerotic lesions.

Animals↗

PubMed1998

The response of smooth muscle cells to alpha-thrombin depends on its arterial origin: comparison among different species.

BACKGROUND: Thrombin plays a pivotal role in the pathogenesis of arterial thrombosis and exerts a wide spectrum of effects on the cells of vessel walls. METHODS: In this paper we focus on the direct role of thrombin as a mitogen for smooth muscle cells (SMCs) derived from different vessels from the vascular tree (coronary artery, aorta, carotid artery and pulmonary artery) of different species (human and pig). All cell populations examined responded mitogenically to alpha-thrombin, however the extent of this response was dependent on both vascular origin and the species from which vessels were derived. RESULTS: Thrombin (1-100 nmol L-1) induced DNA synthesis ranging from 1.5- to 4-fold baseline depending on cell type. Porcine coronary SMCs showed the highest response to thrombin (100 nmol L-1) in terms of protein and DNA synthesis (4.0 +/- 0.2-fold) and cell division (53.4 +/- 8.8%) among the tested cells. In these cells recombinant (r)-hirudin, a specific thrombin inhibitor, exhibited maximal effectiveness to block the mitogenic effect of thrombin. Human SMC response ([3H]-thymidine incorporation) to either sera or thrombin was lower than that of porcine cells. In contrast, c-fos mRNA levels induced by thrombin in human SMCs were higher than those induced in porcine cells. In human cells, thrombin elicited an overexpression of c-fos and a lower rate of [3H]-thymidine incorporation than in porcine cells. Insulin-like growth factor I but not insulin showed additive mitogenic effects with thrombin in human coronary SMCs. The response of these cells to thrombin from different sources was a function of thrombin specific activity. CONCLUSION: These results suggest that the cell system chosen to check thrombin mitogenicity not only determines thrombin quantitative effects but also may affect the effectiveness of an inhibitor to block its biological activity.

Animals↗

PubMed1998

Esterified cholesterol accumulation induced by aggregated LDL uptake in human vascular smooth muscle cells is reduced by HMG-CoA reductase inhibitors.

Vascular smooth muscle cell (VSMC) proliferation is a key event in the development of atherosclerotic lesions. VSMCs synthesize extracellular matrix, where low density lipoproteins (LDLs) are trapped and become aggregated (agLDL). The objective of this study was to investigate the cholesterol uptake and accumulation triggered by agLDL in comparison with native LDL (nLDL) on unstimulated and platelet-derived growth factor-stimulated human aortic VSMCs and the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on these processes. Esterified cholesterol (EC) accumulation induced by agLDL in VSMCs was correlated with the degree of aggregation and concentration. The EC content of VSMCs treated with 100 microg/mL of agLDL (80% aggregated) increased approximately 70-fold over that in VSMCs incubated with the same concentration of nLDL. Whereas nLDL-derived EC was increased approximately twofold in platelet-derived growth factor-stimulated VSMCs, there was no effect of platelet-derived growth factor (10(-9) mol/L) on the uptake of agLDL. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (5 micromol/L) reduced EC accumulation derived from agLDL uptake by 58% and 35% in platelet-derived growth factor-stimulated and unstimulated VSMCs, respectively. This inhibition was overcome by geranylgeraniol (10 micromol/L) and partially by farnesol (10 micromol/L). Fluorescence microscopy of the cellular internalization of agLDL labeled with the fluorochrome 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine demonstrated that simvastatin reduces EC accumulation derived from agLDL by inhibiting its endocytosis and that the effect is completely reversed by geranygeraniol. These results indicate that agLDLs are rapidly internalized by human VSMCs and that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors modulate EC accumulation. These data suggest a possible mechanism by which statins could contribute to the passivation and stabilization of actively growing atherosclerotic lesions.

Cells, Cultured↗

PubMed1998

Purification of the porcine platelet GP IIb-IIIa complex and the propolypeptide of von Willebrand factor.

Platelet membrane glycoproteins (GP) are involved in platelet adhesion and aggregation. The glycoprotein IIb-IIa complex (GP IIb-IIIa) is a Ca2+-dependent heterodimer that binds fibrinogen and other adhesive proteins, thereby mediating platelet aggregation and adhesion. We have purified two major glycoproteins from pig platelets by Concanavalin A-Sepharose, Heparin-Sepharose and Sephacryl S-300 HR chromatography (Fitzgerald et al. Anal Biochem, 1985): i) the GP IIb-IIIa complex, GP IIb Mr = 140,000 and GP IIIa a single chain of Mr = 95,000-100,000; and ii) a predominant glycoprotein of high molecular weight, the propolypeptide of von Willebrand factor (Mr = 80,000-100,000). Western-blot analysis of the purified GP IIb-IIIa showed that only certain monoclonal antibodies against the human receptor specifically recognize the porcine complex. Differences between the porcine and human GP IIb-IIIa glycoproteins could partially explain the decreased inhibitory effects of GP IIb/IIIa-antagonists (against the human receptor) in porcine platelets.

Amino Acid Sequence↗

PubMed1998

Porcine platelet von Willebrand antigen II (vW AgII): inhibitory effect on collagen-induced aggregation and comparative distribution with human platelets.

Von Willebrand factor (vWF) is synthesized by human endothelial cells and megakaryocytes as a large precursor, the pre-provWF, which is finally cleaved into the propolypeptide of vWF (pp-vWF) and the mature vWF. We have purified in parallel the pp-vWF and the GP IIb-IIIa from porcine platelets. The N-terminus comparative analysis of porcine pp-vWF with respect to other species revealed more than a 75% and 65% homology with the bovine and human pp-vWF, respectively. Purified pp-vWF inhibited collagen-induced platelet aggregation in porcine platelet rich plasma (PRP) and specifically binds to collagen. Polyclonal antibody pabBp19 against the purified protein was prepared and characterized by ELISA, Western-blot and immunocytochemistry. The distribution of pp-vWF in soluble and membrane fractions from pig platelets has been performed by immunolabeling detection. pabBp19 did not blot human platelet lysates but human pp-vWF was detectable using the antibody Frieda 013091. Cell distribution and quantification studies of human and porcine platelet pp-vWF showed that the protein exists in the soluble and membrane fractions and its pattern is similar in both species.

Amino Acid Sequence↗

PubMed1997

Tissue factor modulates the thrombogenicity of human atherosclerotic plaques.

BACKGROUND: The thrombogenicity of a disrupted atherosclerotic lesion is dependent on the nature and extent of the plaque components exposed to flowing blood together with local rheology and a variety of systemic factors. We previously reported on the different thrombogenicity of the various types of human atherosclerotic lesions when exposed to flowing blood in a well-characterized perfusion system. This study examines the role of tissue factor in the thrombogenicity of different types of atherosclerotic plaques and their components. METHODS AND RESULTS: Fifty human arterial segments (5 foam cell-rich, 9 collagen-rich, and 10 lipid-rich atherosclerotic lesions and 26 normal, nonatherosclerotic segments) were exposed to heparinized blood at high shear rate conditions in the Badimon perfusion chamber. The thrombogenicity of the arterial specimens was assessed by 111In-labeled platelets. After perfusion, specimens were stained for tissue factor by use of an in situ binding assay for factor VIIa. Tissue factor in specimens was semiquantitatively assessed on a scale of 0 to 3. Platelet deposition on the lipid-rich atheromatous core was significantly higher than on all other substrates (P = .0002). The lipid-rich core also exhibited the most intense tissue factor staining (3 +/- 0.1 arbitrary units) compared with other arterial components. Comparison of all specimens showed a positive correlation between quantitative platelet deposition and tissue factor staining score (r = .35, P < .01). CONCLUSIONS: Our results show that tissue factor is present in lipid-rich human atherosclerotic plaques and suggest that it is an important determinant of the thrombogenicity of human atherosclerotic lesions after spontaneous or mechanical plaque disruption.

Animals↗

PubMed1997

Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells.

3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) are therapeutically used to lower plasma cholesterol levels. In addition, these drugs can block vascular smooth muscle cell (VSMC) proliferation. The present study addressed the question whether the inhibitory effect of lovastatin on premitotic DNA synthesis correlates with a downregulation of c-fos mRNA levels, a marker of signaling efficiency, in human SMC. Here we show that in human SMC exposed to individual growth factors (platelet-derived growth factor, epidermal growth factor, alpha-thrombin, insulin, insulin-like growth factor I (IGF-I)) and human serum, the maximal [3H]thymidine incorporation and c-fos mRNA expression are closely correlated. Only alpha-thrombin elicited overexpression of c-fos as compared with its effect on [3H]thymidine incorporation. Lovastatin efficiently inhibited [3H]thymidine uptake promoted by all mitogens tested (76-87%); however, it significantly inhibited upregulation of c-fos mRNA levels induced only by insulin (33-67%, P < 0.05) and IGF-I (31 57%, P < 0.05). This inhibition was overcome by mevalonate and geranylgeraniol, and partially by farnesol. c-fos mRNA expression induced by 4-beta-phorbol-12-myristate-13-acetate, an activator of protein kinase C, was insensitive to lovastatin treatment. Thus, in human vascular SMC, lovastatin impairs premitotic DNA synthesis induced by growth factors, but only c-fos expression promoted by insulin and IGF-I. These data indicate that statin-sensitive and -insensitive pathways seem to be involved in the regulation of c-fos in the response of human SMC to proliferative stimuli, and suggest a prominent role of isoprenylated proteins in the activation of VSMC through the IGF-I/insulin dependent pathways.

Cells, Cultured↗

PubMed1997

Thrombosis triggered by severe arterial lesions is inhibited by oral administration of a glycoprotein IIb/IIIa antagonist.

Platelet aggregation and thrombosis play an important role in the onset of acute coronary events. Regardless of the stimulus for activation, platelet thrombus formation is ultimately regulated through the IIb/IIIa receptor complex. The effects of oral administration of xemilofiban, a non-peptide mimetic of the RGDF sequence of the IIb/IIIa receptor complex, on thrombus formation were evaluated in a canine model. Xemilofiban significantly reduced platelet deposition on severely damaged arterial wall. Platelet deposition was reduced at both low (13 +/- 1 from 56 +/- 18 x 10(6) platelets cm-2; P < 0.05) and high (23 +/- 2 from 111 +/- 21 x 10(6) platelets cm-2; P < 0.01) shear rates. Platelet deposition was reduced to a monolayer as seen by electron microscopy (platelet-vessel wall interaction). Therefore, the availability of an orally active IIb/IIIa antagonist for chronic use may have significant value in preventing thrombus formation in those clinical situations associated with severe arterial injury, such as atherosclerotic plaque disruption.

Administration, Oral↗

PubMed1997

Monounsaturated and polyunsaturated n-6 fatty acid-enriched diets modify LDL oxidation and decrease human coronary smooth muscle cell DNA synthesis.

Proliferation of smooth muscle cells (SMCs) plays an important role in atherosclerotic lesion progression. The purpose of this investigation was to examine the effect of diets differing in fatty acid composition on human coronary SMC entry in the cell proliferation cycle. Twenty-four healthy men and women were placed on four consecutive diets lasting 5 weeks each: (1) saturated fatty acid (SFA)-rich diet with palm oil; (2) monounsaturated fatty acid (MUFA)-rich diet with olive oil; (3) polyunsaturated fatty acid (PUFA) n-6-rich diet with sunflower oil; and (4) PUFA n-3-rich diet (3.8 g/d). All diets supplied 35% of calories as fat. Compared with the SFA diet, all unsaturated diets reduced LDL cholesterol. Resistance of LDL to oxidative modification was significantly increased during the MUFA period (P < .05). Human coronary SMCs were cultured and induced by sera derived from the different groups. 3H-Thymidine incorporation into doubling DNA was significantly (P < .01) reduced during the MUFA and PUFA n-6 periods but not during the PUFA n-3 diet with respect to the SFA diet. This effect was more pronounced in women than in men. In conclusion, the MUFA-enriched diet reduced SMC DNA synthesis and LDL levels and protected LDL from oxidation. Therefore, these combined effects suggest that an oleic acid-rich Mediterranean diet could be better than PUFA (n-6)- or PUFA (n-3)-rich diets in the prevention of atherosclerosis.

Cell Division↗

PubMed1997

HDL-induced prostacyclin release in smooth muscle cells is dependent on cyclooxygenase-2 (Cox-2).

Cyclooxygenase-1 (Cox-1) and Cox-2 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. We studied the effects of plasma HDL and LDL on the synthesis of prostacyclin, Cox-1/Cox-2 mRNA, and protein expression by rabbit aortic smooth muscle cells. Prostacyclin synthesis was measured by enzyme immunoassay (EIA) of the stable metabolite of prostacyclin (PGI2), 6-ketoprostaglandin F1 alpha. HDL (150 micrograms/mL) induced release of PGI2 to values 3.46 +/- 0.3-fold above control. Incubations with LDL did not induce release of PGI2. N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS-398), a selective irreversible Cox-2 inhibitor, blocked the HDL-induced PGI2 synthesis. Cycloheximide, actinomycin D, and dexamethasone downregulated HDL-induced PGI2 synthesis; therefore, HDL induced de novo synthesis of protein and Cox-2 mRNA. In addition, Northern blot analyses did not reveal differences in Cox-1 mRNA levels between control and HDL-treated cells, whereas Cox-2 mRNA levels were significantly increased in treated cells. Western blot analysis also showed an increase in the levels of Cox-2 protein. Therefore, the effects of HDL on PGI2 synthesis are mediated via upregulation of Cox-2 expression.

Amino Acid Sequence↗

PubMed1997

Models to study thrombotic disorders.

Experimental models of thrombosis and vascular injury are important research resources that have enhanced our understanding of this pathophysiological process. Animal models provide insights into the prevalence of mechanisms that have been outlined in isolated cell and protein studies. The availability of transgenic and gene knockout animals will allow to pinpoint the relative functional importance of single changes in specific gene products in the pathophysiological process. The advances generated in our understanding of vascular injury and blood interaction with the vascular wall will facilitate the formulation of new strategies for cardiovascular protection an the prevention and treatment of thrombosis. The importance of thrombosis is highlighted by its dramatic consequences, which are the concern of numerous studies aimed at improving both treatment and diagnosis (1-3). Ultimately these studies are based on the evolving research on the mechanisms of thrombus formation. Blood factors, vessel wall factors, and cell-cell interactions in the context of fluid dynamics regulate thrombus formation and should be thoroughly investigated.

Animals↗

PubMed1996

A mimetic of the RGDF-peptide [arginine-glycine-aspartic acid-phenylalanine] blocks aggregation and flow-induced platelet deposition on severely injured stenotic arterial wall. Effects on different animal models and in humans.

8-Guanidino-octanoyl-aspartic acid-phenylalanine (SC-49992), a mimetic of the tetrapeptide arginine-glycine-aspartic acid-phelylalanine, inhibits fibrinogen and vitronectin binding to GP IIb/IIIa. SC-49992 effects on impedance and optical aggregation were compared in different species (human, porcine and dog), SC-49992 induced significant inhibition both in whole blood and PRP aggregation, in all species; however, porcine platelets had a SC-49992 IC50 = 2.5 mM while human and dog platelets had a significant lower IC50 (1 microM and 1.5 microM, respectively). Inhibition of flow-mediated platelet deposition on severely injured vessels was studied in porcine blood at high and low shear rates for 5 minutes. Additionally, studies were performed in vessels with 80% stenosis. SC-49992 reduced platelet deposition both at high and low shear rate in parallel streamlined flow and in stenotic conditions. The lower affinity of porcine platelets for SC-49992 seems to be due to a species difference at the GPIIb/IIIa receptor RGD-sequence level.

Amino Acid Sequence↗