摘要:

Both platelets and neutrophlls interact with the injured vessel wall and may contribute to thrombosis and vasospasm. The effect of platelets on neutrophil interactions with the vessel wall was studied in normal and thrombocytopenic pigs. "Cr-labeled platelet deposition (xlO') and '"In-labeled neutrophil deposition (xlO3) on undamaged aortic strips with intact endothelium or damaged aortic strips with exposed media were quantified in superfusion flow chambers before and after platelet depletion by specific rabbit antisera. Arterial blood was drawn at a constant flow rate through the superfusion chambers at 37°C. Under basal conditions, platelets did not adhere to the uninjured vessel wall with intact endothelium, whereas neutrophil interaction with the endothelium was low and constant at shear rates of 427, 853, and 1280 s"1and did not change significantly after thrombocytopenia. On exposed aortic media simulating deep arterial injury, platelet deposition increased over these shear rates from 14.0±3.4 to 37.5 ±12.0 (p<.05) to 68.0±9.0, respectively (p<.05). Similarly, neutrophil deposition on the media increased from 48.7±8.7 to 73.7±14J (P<.0S) to 118-3±22.9, respectivelyp) <.O5). Platelet deposition on the media did not occur after thrombocytopenia (80% reduction in platelet count); however, neutrophil deposition persisted, but was less intense and was now independent of shear rates (233 ±S3. at 427 s"1, 18.7±3.2 at 853 s~', and 24.1 ±3.9 at 1280 s~'; not significant). Additionally, after platelet depletion, neutrophil aggregation with iV-fonnyl-methionyl-leucyl-phenylalanlne (2 × 10"* mol/L) in vitro was inhibited. These results indicate that platelets modulate neutrophil deposition on the exposed aortic media. Under thrombocytopenic conditions, a low level of neutrophil deposition can be unmasked in the absence of any platelet deposition. Neutrophils may thus interact directly with the vessel wall to promote vascular changes independent of platelets.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Catecholamine stimulation of lipolysis through adipocyte ftadrenoceptors is of major importance for the regulation of lipid mobilization from adipose tissue. The influence of adipocyte 0-receptor sensitivity as assessed by an isoprenaline bioassay on circulating lipid levels was investigated in 46 healthy and drug-free subjects. /9-Receptor sensitivity was inversely related to total plasma triglycerides (r=−.62), very low density lipoprotein cholesterol (VLDL-C) (r=−.56), VLDL triglycerides (r=−.52), and apolipoprotein B (r=&#151;.41). These relationships remained significant after adjustment for age, sex, body mass index, waist/hip ratio, fat cell volume, and circulating levels of insulin, noradrenaline, and adrenaline. ftReceptor sensitivity accounted for 40% of the variance in total plasma triglycerides. ftReceptor subtype sensitivity and binding capacity were also determined in fat cells using terbutaline (ft) and dobutamine (ft) bioassays and radioligand binding. Multiple regression analysis revealed that terbutaline sensitivity correlated inversely with total plasma triglycerides, apolipoprotein B, VLDL-C, and VLDL triglycerides (partial r from &#151;.56 to &#151;.42), but there was no correlation between dobutamine sensitivity and blood lipids (partial r from.05 to .18) or between receptor binding and blood lipids (partial r from .01 to 28). Thus, the llpolytic β-receptor sensitivity in fat cells appears to play a hitherto-unrecognized role for lipoprotein metabolism, in particular that of VLDL. This relationship is receptor-subtype specific, particularly involving ft-receptors, and seems to be localized to a postreceptor step in lipolysis regulation. Low sensitivity may be of importance for the development of hypertriglyceridetnia.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Although most subjects with familial defective apolipoprotein B-100 (FDB) have raised plasma low-density lipoprotein (LDL) levels, a few have LDL levels within the normal range. We have previously identified two normocholesterolemic FDB heterozygotes in an affected family. Results obtained from a study of this family are compatible with a major genetic contribution to the normocholesterolemia in the two heterozygotes. However, our findings are not compatible with inheritance of a variant normal allele at the apolipoprotein B locus in this family that neutralizes the effect of an FDB allele on the plasma LDL level. Polymorphic variations at the apolipoprotein E and LDL receptor loci did not explain the presence of normal LDL levels in the two heterozygous FDB subjects.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The purpose of this study was to relate local blood flow conditions to the development of poststenotic dilatation (PSD) in the common carotid arteries of rabbits. We investigated the effects of the geometry of the stenoses on PSD formation to gain insight into the mechanisms of this phenomenon. With short stenoses, the maximum diameter of the PSD after 3 weeks increased from about 25% to 50% above the proximal diameter by increasing the severity of the stenoses from 50% to 60% diameter reduction. By contrast, increasing the length of the constricted region of 60% stenoses did not affect the PSD, and in all cases, the site of maximum dilatation occurred within 3 tube diameters from the stenoses. In vitro studies were conducted with the photochromic tracer technique. The most striking observation was that the transition to turbulence did not occur with a 55% short stenosis. By increasing the severity of this short stenosis to 70%, the transition to very localized turbulence was triggered =6 to 8 tube diameters from the stenosis during the early deceleration phase of the flow cycle. The transition point moved farther downstream by increasing the length of this moderate stenosis. This study demonstrated that PSD can occur under turbulence-free conditions, and even when turbulence was generated, the site of the PSD was remote from that of the localized turbulence zone. The wall shear stress pattern was determined for the long 60% stenosis. When compared with the values measured upstream from the stenosis, the wall shear stress within the throat was estimated to be at least 30 times larger, whereas downstream from the stenosis, it was roughly two times larger, together with strong cycle-to-cycle variations. We hypothesize that extreme magnitudes of the shear stress or shear stress variations in the throat of the stenosis or in the poststenotic region can give rise to PSD formation, probably by stimulating the release of agents that induce vessel wall remodeling when delivered to tissues around the poststenotic primary vortex. It is more likely that shear stresses in the stenosis throat than in the downstream region are important, since both shear stresses at the throat and the degree of PSD were sensitive to degree of stenosis, whereas downstream shear stresses were not PSD is not initiated by shear-induced release of endothelium-derived relaxing factor; experiments with an inhibitor of endothelium-derived relaxing factor synthesis, the argjnine analogue /VG-nitro-L-argiiiine-methyl ester, failed to influence the development of PSD.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Many studies of the endothelium have assumed equivalence between cultured confluent cells and an endothelial lining in vivo. We compared gene expression of bovine aortic endothelial cells (BAECsJ in culture versus freshly isolated cells from bovine aortas. Our technique of harvesting in vivo tissue yielded cells that were endothelial by the criteria of their containing von Willebrand factor (vWF) and lacking smooth muscle ar-actin, by both immunocytochemistry and tnRNA analyses. We found that several genes are overexpressed when BAECs are placed into culture, including basic fibroblast growth factor, platelet-derived growth factor B-chain, and thrombospondin. On the other hand, message for vWF is highly expressed in vivo and at lower levels in confluent cultures. The transcripts for transforming growth factor-/}, plakoglobin,and Jig (fins-likegene, FGF receptor-1) are comparable in vitro and in vivo. These results demonstrate that significant changes in gene expression occur in the transition from in vivo conditions to tissue culture of endothelial cells. Studies of in vitro endothelium may poorly reflect a quiescent endothelial lining in vivo but may be more similar to cells responding to injury or angiogenic stimuli.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Excessive proliferation and overexpresslon of collagens by smooth muscle cells (SMCs) are important features of atherogenesis. To understand the role of the extracellular matrix in the regulation of these processes, we examined proliferation and protein/collagen synthesis of SMCs in contact with a collagen matrix. Adult pig SMCs were isolated from the aortic media by collagenase digestion, subcultured as monolayers, and then embedded into a three-dimensional network of type I collagen, ie, a collagen lattice. Cells were subsequently exposed to growth-promoting media, and their behavior was observed in comparison with monolayer cultures on plastic Treatment of monolayers with increasing concentrations of fetal calf serum resulted in activation of the cell cycle, onset of cell proliferation, and increased protein/collagen synthesis. In contrast, similar treatment of collagen lattice-cultured SMCs failed to influence cell proliferation and protein/collagen synthesis. However, stimulation of proliferation of lattice-cultured SMCs by platelet-derived growth factor-A/B was feasible; nevertheless, the rate of proliferation was modest compared with monolayers. In addition, the onset of proliferation was accompanied by a decrease in collagen synthesis of the cells. Thus, a collagenous matrix appears to suppress the responsiveness of SMCs to soluble growth mediators. It is speculated that interactions between SMCs and the extracellular matrix may modify proliferation and protein/collagen synthesis of cells not only in vitro but also in vivo during atherogenesis by making and breaking binding sites between extracellular collagen and matrix receptors.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

HOE- 402 (4 -amlno-2 - [4,4 -dimethyl-2 -oxo-1 -imldazolldinyl] -pyrimldlne- 5 -A'- [trifluoromethylphenyl] - carboxamide-monohydrochloride) has been shown to exhibit hypolipidemic action in heterozygous Watanabe heritable hyperlipidemic rabbits. In all animals, elevated cholesterol levels were reduced to normal (from 3.0 to 1.5 mmol/L) after 3 weeks of HOE- 402 treatment This was due entirely to reduction of low density lipoprotein (LDL) cholesterol and was paralleled by accelerated removal of plasma '"I-LDL. This reduction of LDL levels was not found in homozygous LDL receptor-defective animals, emphasizing the necessity of a functional LDL receptor system for the hypolipidemic action. The effect of HOE-402 on LDL receptor activity in the cultured hepatoma cell line HepG2 was also determined. When cells were incubated with plasma from treated animals (containing cholesterol 1.5 mmol/L and HOE- 402 80 ng/mL), high-affinity cell-surface binding sites for LDL were induced more than threefold, as shown by Scatchard analysis of cell-surface binding data. Induction of the LDL receptor was detectable after 6 hours and was 300% after 18 hours. This induction was specific for LDL, as '"I-transferrin and ["Feltransferrin were internalized normally in HOE-402-treated cells. The increase of LDL receptor protein was related to induced LDL receptor mRNA levels (400%), as shown by quantification of Northern blotting experiments. These findings suggest that HOE-402 mediated its hypolipidemic action mainly via the LDL receptor pathway. It enhanced mRNA levels for LDL receptor, hence increasing its synthesis, which subsequently resulted in reduced plasma LDL levels. Apart from having pharmacological implications, this compound could be very useful in elucidating the components that regulate the gene expression of the LDL receptor.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Leukocyte adhesion and subendothelial emigration, constant hallmarks of early atherogenesis, have been ascribed to the action of oxidized low-density lipoprotein (oxLDL). Using intravital fluorescence microscopy in the skinfold-chamber model in hamsters, we have previously shown that systemic administration of oxLDL stimulates leukocyte adhesion in vivo through a mechanism that depends on the generation and/or action of both leukotrienes and superoxide radicals. On the basis of the fact that oxygen radical-catalyzed peroxidation of phospholipids results in the generation of fragments with shortsn2residues, which besides authentic platelet-activating factor (PAF), activate the receptor for PAF on leukocytes and thereby induce leukocyte adhesion, we asked whether pretreatment of hamsters with a specific PAF receptor antagonist (WEB2170; 1 mg/kg of body weight IV, 10 minutes before oxLDL) attenuates leukocyte adhesion after injection of oxLDL (4 mg/kg of body weight IV, oxidized by 7.5 /unol/L CuJ+for 18 hours at 3TC). We demonstrate herein that in contrast to untreated control animals in which oxLDL elicited rolling and adhesion of circulating leukocytes to the endothelium of venules and arterioles, oxLDL-induced leukocyte adhesion was significantly attenuated in WEB2170-pretreated animals. These changes cannot be ascribed to alterations of microhemodynamic parameters and, hence, wall shear conditions. This finding indicates that oxLDL-induced leukocyte/endothelium interaction involves the PAF receptor, which may function both as a receptor for authentic PAF or for PAF-Iike lipids that are generated in a free radical-catalyzed peroxidation of phospholipids.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Rat aortic allografts from the DA (RT1*) to the WF (RTlr) strain but not syngenelc DA-to-DA control grafts develop arteriosclerotic changes in the vascular wall that are virtually identical to human allografts during chronic rejection. A more prominent medial cell destruction in the rat aorta, leading ultimately to complete medial necrosis, is the major difference between rat and human allografts. If the adventitia of syngeneic grafts is exposed to starch before transplantation, these grafts also develop an inflammatory reaction in the adventitia and an extensive intimal thickening at the site of the granulomas, but the medial smooth muscle cells are preserved. In both types of transplants with an intact endothelium as determined by light microscopy, adventitial inflammatory cell proliferation was accompanied by smooth muscle cell replication in the media and thickening of the intima. We therefore propose that an adventitial proliferative response is a prerequisite for intimal thickening to occur. In the allograft but not in starch-exposed syngeneic grafts there was also a notable tymphoid activation in the adventitia, which was accompanied by medial necrosis. We suggest that the medial necrosis in the allograft is linked to a toxic effect of activated lymphoid cells on medial myocytes and is not a prerequisite for intimal proliferation. Instead, intimal proliferation and medial necrosis in the allograft seem to be independently regulated.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Platelet-derived growth factor (PDGF) and transforming growth factor-/3, (TGF-/3,), two growthregulatory peptides with opposite effects on arterial smooth muscle cell (ASMC) proliferation, were examined for their influence on the synthesis of two small chondroitin sulfate/dermatan sulfate proteoglycans (CS/DS PGs) called biglycan and decorin. Quiescent ASMCs treated with either PDGF or TGF-0] for 24 hours increased [MS] sulfate incorporation into biglycan 3.3- and 2.9-fold, respectively, whereas the incorporation of [MS] sulfate into decorin was not significantly affected. Treatment with TGF-/3, but not PDGF more than doubled the steady-state level of messenger RNA (mRNA) transcripts hybridizing to a complementary DNA (cDNA) encoding biglycan. Both growth factors had little or no effect on steady-state levels of mRNA transcripts hybridizing to a decorin cDNA. Incorporation of ["S] sulfate into biglycan glycosaminoglycan (GAG) was maximal by 12 to 18 hours after either PDGF or TGF-ft addition. Both PDGF and TGF-0, increased the molecular sizes of biglycan and decorin. This increase was a result of the synthesis of longer GAG chains substituted on the core proteins of both PGs. PDGF but not TGF-ft led to an increase or more than twofold in the ratio of 6′- to 4-sulfated disaccharides in these newly synthesized GAG chains. These results indicate that PDGF and TGF-0, have specific but different effects on the synthesis of small CS/DS PGs by monkey ASMCs in culture.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID