Biomedical subjects

Lina Badimon

Publications and source records attributed to Lina Badimon.

28 records · Page 2Linked to original sources

PubMed2004

The unsaponifiable fraction of virgin olive oil in chylomicrons from men improves the balance between vasoprotective and prothrombotic factors released by endothelial cells.

Minor components of virgin olive oil (VOO) may play a key role in the beneficial effects of VOO on atherosclerosis. In the present study we evaluated the influence of the unsaponifiable fraction of VOO on the production of eicosanoids and nitric oxide (NO) by endothelial cells (HUVECs). Triglyceride-rich lipoprotein (TRLs) were isolated from human serum after the intake of meals enriched in 3 high-oleic acid oils, i.e., high-oleic sunflower (HOSO), VOO, or enriched-virgin olive (EVO) oils, the last-mentioned containing 2.4% of unsaponifiable matter. HOSO induced a greater accumulation of triglycerides (TGs) in the postprandial serum than VOO or EVO, as measured by calculating the area under the curve. The incubation with TRLs increased NO release by endothelial cells compared with untreated control cells, but the effects of the various TRLs did not differ. EVO-derived TRLs reduced the production of prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TxB(2)) (the stable metabolite of TxA(2)) compared with VOO- or HOSO-derived TRLs. The release of PGI(2) (as 6-keto PGF(1alpha)) was similarly diminished by all TRLs compared with the control. In conclusion, the unsaponifiable fraction of VOO does not affect postprandial triglyceridemia, but it has favorable effects on endothelial function, mainly by reducing proinflammatory and vasoconstrictor eicosanoid synthesis (PGE(2) and TxB(2)).

Adult↗

PubMed2004

Antithrombotic effects of saratin on human atherosclerotic plaques.

Platelets play a primary role in thrombus formation after plaque rupture. Platelets recognize the exposed collagen via Von Willebrand factor (VWF) and become activated. Saratin, an inhibitor of the VWF-dependent binding of platelets to collagen, may reduce the thrombotic risk associated to atherosclerosis. Our objective was to evaluate the antithrombotic effects of local treatment with saratin on human atherosclerotic lesions. Thrombus formation was assessed by the deposition of (111)In-platelets on different human atherosclerotic lesions under three local shear conditions (800,1700 and 3400/s) with blood derived from catheterized pigs. Human atherosclerotic lesions were locally treated with saratin (30 microg/ml) at 37 degrees C for 5 min and placed in the chamber. Under stenotic shear conditions of 800/s, saratin significantly (p<0.05) reduced platelet deposition triggered by human denuded vessel wall (44%), fatty streaks (47%), severely damaged vessel (50%) and atherosclerotic plaque (57%). Thrombus characterization by immunohistochemistry showed also a reduction in fibrin deposition in treat-ed vessels. These results suggest that the local site-specific treatment with saratin inhibits atherosclerotic plaque thrombogenicity at haemodynamic conditions typical of moderately stenotic coronary arteries.

Animals↗

PubMed2004

A novel anti-ischemic nitric oxide donor inhibits thrombosis without modifying haemodynamic parameters.

Platelets are involved in the clinical presentations of ischemic heart disease. Our objective was to study the antithrombotic effects of a new nitric oxide donor (LA419), a neutral sugar organic nitrate with a protected thiol group in its molecular structure. Animals were randomly distributed in three groups: I) oral administration of LA419 (0.9-1.8-3.6-5 mg/kg/d, 10 days); II) oral administration of standard IS-5-MN (0.9-1.8 mg/kg/d, 10 days); III) non-treated group (control). In catheterized pigs, thrombosis was studied under controlled rheological conditions by radioisotopic evaluation of deposited platelets on damaged vessel wall, placed in an extracorporeal perfusion chamber. Changes in blood pressure, heart rate, and platelet aggregation were evaluated. Results have shown that LA419 significantly decreased thrombus formation according to the degree of vascular damage, and shear rate conditions in a dose-dependent manner (p<0.005), without significant modifications on blood pressure and/or elevation of liver enzymes. In contrast, IS-5-MN only showed a significant reduction on platelet deposition at the high dose, that was associated to hypotension and elevation of liver enzymes. Therefore, we conclude that this new anti-ischemic NO-donor (NOd) LA419 that inhibits platelet function without modifying blood pressure may be a highly efficacious strategy to passivate platelet activation induced by a damaged vessel wall.

Administration, Oral↗

PubMed2003

Neuron-derived orphan receptor-1 (NOR-1) modulates vascular smooth muscle cell proliferation.

Vascular smooth muscle cells (VSMCs) migration and proliferation play a key role in the pathophysiology of cardiovascular disease. However, the transcription factors that regulate VSMC activation are not completely characterized. By a mRNA-differential display approach, we have identified neuron-derived orphan receptor-1 (NOR-1), a transcription factor within the NGFI-B subfamily of nuclear receptors, as a immediate-early gene in VSMCs. Two NOR-1 isoforms (alpha and beta) were identified and cloned from serum-induced porcine VSMC that shared high homology with the human isoforms. Northern blot analysis revealed a strong and transient (1 to 6 hours) upregulation of NOR-1 in both porcine and human coronary SMCs by growth factors (serum, platelet-derived growth factor-BB, and epidermal growth factor) and alpha-thrombin but not by cytokines. NOR-1 upregulation is processed through G protein-coupled receptors and tyrosine kinase receptors, and involves Ca2+ mobilization, protein kinase C activation, and the mitogen-activated protein kinase pathway. This induction was closely dependent of the cAMP response elements present in NOR-1 promoter as transfection assays indicate. Human coronary atherosclerotic lesions overexpress NOR-1, and balloon angioplasty transiently induces NOR-1 in porcine coronary arteries with a pattern similar to that observed in VSMCs in culture. Antisense oligonucleotides against NOR-1 inhibited human coronary SMC proliferation (reduced de novo DNA synthesis, cell cycle progression, and VSMC wound repair) as efficiently as antisense against the protooncogene c-fos. These results show that NOR-1 modulates VSMC proliferation, and suggest that this transcription factor may play a role in both spontaneous and accelerated atherosclerosis.

3T3 Cells↗

PubMed2003

Differential intracellular trafficking of von Willebrand factor (vWF) and vWF propeptide in porcine endothelial cells lacking Weibel-Palade bodies and in human endothelial cells.

Von Willebrand factor (vWF) is an adhesive protein involved in primary haemostasis virtually absent in the thoracic aorta of swine, an animal model widely used in thrombosis and atherosclerosis. By RT-PCR analysis we show that porcine aortic endothelial cells (PAEC) express the vWF gene, although vWF mRNA levels were 8+/-0.8-fold (p<0.05) or 290+/-8.9-fold (p<0.0001) lower than those in porcine pulmonary artery EC (PPEC) or human aortic EC (HAEC), respectively. Although vWF was rare in the thoracic aorta of swine, vWF propeptide (vWFpp) was present in the endothelium of this artery and in both primary and passaged PAEC. In addition, vWFpp but not vWF was detected in PAEC by Western blot. In PAEC neither vWFpp nor P-selectin immunostaining depicted Weibel-Palade bodies (WPB)-like structures, and acute stimuli (alpha-thrombin or the calcium ionophore A23187) did not increase vWF secretion. vWFpp co-localized with a Golgi marker, that cycles between the stacked Golgi (SG fraction) and earlier compartments of the secretory pathway. Our results confirm that PAEC express very low levels of vWF mRNA and indicate that in these cells, that do not have WPB, vWF and vWFpp have divergent intracellular trafficking pathways.

Animals↗

PubMed2003

[Neovascularization in human coronary arteries with lesions of different severity].

INTRODUCTION AND OBJECTIVES: Endothelial function can be modulated by growth factors produced by activated smooth muscle cells, inflammatory cells and plasma products that infiltrate the lesion. The aim of this study was to quantify neovessels in human coronary arteries with atherosclerotic lesions of different severity and analyze their relationship with inflammatory cell and plasma product infiltrates. PATIENTS AND METHOD: We studied 60 coronary arteries from patients who underwent heart transplant. Cellular markers (smooth muscle cell, monocyte/macrophage), the presence thrombin/prothrombin and expression of vascular endothelial growth factor (VEGF) were analyzed and quantified by conventional histology, immunohistochemistry and image analysis techniques. RESULTS: Neovessels were detected in advanced lesions, and a positive correlation was observed with the degree of vessel remodeling, monocyte/macrophage infiltration and lipid deposition. Smooth muscle cells were the main producers of VEGF in both the intima and media layers of advanced lesions. In these lesions thrombin/prothrombin-positive areas colocalized with activated smooth muscle cells. CONCLUSIONS: The presence of neovessels in coronary arteries correlated with inflammatory cell infiltration, lipid deposition and thrombin/prothrombin content. VEGF expression was mainly associated with smooth muscle cells, indicating a key role of these cells in the modulation of endothelial cell function.

Adolescent↗

PubMed2002

Low-density lipoprotein upregulates low-density lipoprotein receptor-related protein expression in vascular smooth muscle cells: possible involvement of sterol regulatory element binding protein-2-dependent mechanism.

BACKGROUND: Low-density lipoprotein (LDL) receptor-related protein (LRP) is highly expressed in vascular smooth muscle cells (VSMCs) of both normal and atherosclerotic lesions. However, little is known about LRP regulation in the vascular wall. METHODS AND RESULTS: We analyzed the regulation of LRP expression in vitro in human VSMCs cultured with native LDL (nLDL) or aggregated LDL (agLDL) by semiquantitative reverse transcriptase-polymerase chain reaction, real-time polymerase chain reaction, and Western blot and in vivo during diet-induced hypercholesterolemia by in situ hybridization. LRP expression in human VSMCs is increased by nLDL and agLDL in a time- and dose-dependent manner. Maximal induction of LRP mRNA expression was observed after 24 hours of exposure to LDL. However, agLDL induced higher LRP mRNA expression (3.0-fold) than nLDL (1.76-fold). LRP mRNA upregulation was associated with an increase on LRP protein expression with the greatest induction by agLDL. VSMC-LRP upregulation induced by nLDL or agLDL was reduced by an inhibitor of sterol regulatory element binding protein (SREBP) catabolism (N-acetyl-leucyl-leucyl-norleucinal). In situ hybridization analysis indicates that there is a higher VSMC-LRP expression in hypercholesterolemic than in normocholesterolemic pig aortas. CONCLUSIONS: These results indicate that LRP expression in VSMCs is upregulated by intravascular and systemic LDL.

Animals↗

PubMed2002

Differential role of heparan sulfate proteoglycans on aggregated LDL uptake in human vascular smooth muscle cells and mouse embryonic fibroblasts.

OBJECTIVE: Low density lipoprotein (LDL) receptor-related protein (LRP) binds and internalizes aggregated LDL (agLDL) in human vascular smooth muscle cells (VSMCs). To analyze the contribution of proteoglycans (PGs) to agLDL uptake in human VSMCs, in wild-type mouse embryonic fibroblasts (MEF line), and in LRP-deficient mouse embryonic fibroblasts (PEA13 line). METHODS AND RESULTS: PGs in the medium and cellular and extracellular matrix have been isolated by metabolic radiolabeling with [35S]Na2SO4 and characterized by selective digestion with heparinase I and III (4 U/mL each) and chondroitinase ABC (2 U/mL). To examine the contribution of PGs and LRPs to agLDL internalization, nonexpressing and LRP-expressing cells, treated or not with polysaccharidase, were incubated with agLDL (25, 50, and 100 micro g/mL) for 18 hours. In human VSMCs, agLDL was unable to induce cholesteryl ester (CE) accumulation in antisense LRP-oligodeoxynucleotide-treated cells, and heparan sulfate (HS)-PG depletion leads to a reduction of the CE accumulation. In mouse fibroblasts, PEA13 compared with MEF showed lower, but still considerable, CE accumulation, and HS-PG depletion almost completely inhibited CE accumulation. CONCLUSIONS: In MEF, HS-PGs can function alone as receptors that bind and internalize agLDL in the absence of LRP, but in human VSMCs, although HS-PGs facilitate agLDL binding to the cells, LRP is essential for agLDL internalization.

Animals↗

PubMed2002

Low density lipoproteins downregulate lysyl oxidase in vascular endothelial cells and the arterial wall.

OBJECTIVE: Hypercholesterolemia induces endothelial dysfunction, a hallmark of the atherosclerotic process, modulating the expression of key genes in vascular endothelial cells. METHODS AND RESULTS: By differential display analysis, we have studied the effect of high concentrations of native low density lipoprotein (LDL) on endothelial gene expression. mRNA levels of lysyl oxidase (LOX), an enzyme involved in collagen and elastin cross-linking, were downregulated by LDL treatment in endothelial cells in a dose- and time-dependent manner (80% of inhibition by 180 mg/dL LDL for 24 hours). This reduction of LOX expression was associated with a decrease in LOX activity (40% and 54% of inhibition after 24 and 48 hours of LDL treatment, respectively). LOX mRNA half-life was not modified by LDL, but transcriptional inhibition blocked the effect of LDL. Inhibition of LOX activity by either LDL or beta-aminopropionitrile, an inhibitor of LOX, increased endothelial permeability (192+/-0.19- and 3.37+/-0.74-fold, respectively). Interestingly, a reduction in LOX expression (3.5-fold) was observed in vivo in the vascular wall of hypercholesterolemic pigs. CONCLUSIONS: These findings suggest that LDL downregulation of LOX could contribute to the endothelial dysfunction caused by hypercholesterolemia, thus contributing to atherosclerotic plaque formation.

Animals↗

PubMed2002

Human coronary smooth muscle cells internalize versican-modified LDL through LDL receptor-related protein and LDL receptors.

Versican-like proteoglycans are the main component of the intimal extracellular matrix interacting with low density lipoprotein (LDL). The aim of this study has been to investigate the receptors involved in versican-modified LDL uptake by human vascular smooth muscle cells (VSMCs). We have found that versican-LDL interaction leads to the following: (1) monomeric LDL particles that are similar in size and electrophoretic mobility to native LDL but that have a higher capacity to induce intracellular cholesteryl ester (CE) accumulation and (2) fused LDL particles similar in size to those obtained by vortexing. The precipitable fraction of versican-LDL, composed of 50% monomeric and 50% fused LDL particles, induced a dose-response increase in the CE content of VSMCs. Anti-LDL receptor antibody decreased the CE accumulation derived from monomeric LDL particles by 88 +/- 3% and that derived from the total precipitable fraction by 45 +/- 3%. Inhibition of LDL receptor-related protein expression by antisense oligodeoxynucleotides reduced the CE accumulation derived from the precipitable fraction by 65 +/- 2.8%, whereas it did not produce any effect on the CE accumulation derived from monomeric LDL. These results suggest that versican-LDL induces CE accumulation in human VSMCs by the LDL receptor (monomeric particles) and LDL receptor-related protein (fused LDL).

Cell Membrane↗