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B Cercek

Publications and source records attributed to B Cercek.

At least 37 records · Page 2Linked to original sources
PubMed1999

Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators.

BACKGROUND: Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and that its expression is regulated by proinflammatory molecules. METHODS AND RESULTS: MT1-MMP expression was examined in normal and atherosclerotic human arteries by immunocytochemistry with specific antibodies. MT1-MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in response to proinflammatory molecules (interleukin [IL]-1alpha, tumor necrosis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipitation for protein, and gelatin zymography for catalytic activity. Medial SMCs of normal vessel wall expressed MT1-MMP. In atherosclerotic arteries, MT1-MMP expression was noted within the complex atheroma colocalizing with SMCs and macrophages (Mphi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-dependent manner within 4 to 8 hours of exposure to IL-1alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expression by human monocyte-derived Mphi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha. CONCLUSIONS: This study demonstrates that MT1-MMP, an activator of pro-MMP-2, is expressed by SMCs and Mphi in human atherosclerotic plaques. Furthermore, proinflammatory molecules upregulate MT1-MMP expression in vascular SMCs and Mphi. Thus, activation of SMCs and Mphi by proinflammatory molecules may influence extracellular matrix remodeling in atherosclerosis by regulating MT1-MMP expression.

Antibodies, Monoclonal↗
PubMed1999

Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages.

BACKGROUND: Macrophages in human atherosclerotic plaques produce a family of matrix metalloproteinases (MMPs), which may influence vascular remodeling and plaque disruption. Because oxidized LDL (ox-LDL) is implicated in many proatherogenic events, we hypothesized that ox-LDL would regulate expression of MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in monocyte-derived macrophages. MWRHOSA AND RESULTS: Mononuclear cells were isolated from normal human subjects with Ficoll-Paque density gradient centrifugation, and adherent cells were allowed to differentiate into macrophages during 7 days of culture in plastic dishes. On day 7, by use of serum-free medium, the macrophages were incubated with various concentrations of native LDL (n-LDL) and copper-oxidized LDL. Exposure to ox-LDL (10 to 50 microg/mL) increased MMP-9 mRNA expression as analyzed by Northern blot, protein expression as measured by ELISA and Western blot, and gelatinolytic activity as determined by zymography. The increase in MMP-9 expression was associated with increased nuclear binding of transcription factor NF-kappaB and AP-1 complex on electromobility shift assay. In contrast, ox-LDL (10 to 50 microg/mL) decreased TIMP-1 expression. Ox-LDL-induced increase in MMP-9 expression was abrogated by HDL (100 microg/mL). n-LDL had no significant effect on MMP-9 or TIMP-1 expression. CONCLUSIONS: These data demonstrate that unlike n-LDL, ox-LDL upregulates MMP-9 expression while reducing TIMP-1 expression in monocyte-derived macrophages. Furthermore, HDL abrogates ox-LDL-induced MMP-9 expression. Thus, ox-LDL may contribute to macrophage-mediated matrix breakdown in the atherosclerotic plaques, thereby predisposing them to plaque disruption and/or vascular remodeling.

Collagenases↗
PubMed1999

Leukaemia inhibitory factor enhances tissue factor expression in human monocyte-derived macrophages: a gp130-mediated mechanism.

Leukaemia inhibitory factor (LIF) and interleukin (IL)-6 are members of a cytokine group that share a common signal transducer gp130 and induce pleiotropic biological effects in cells of diverse lineage. In monocytes, LIF facilitates differentiation, which may stimulate the biosynthesis of tissue factor (TF) that initiates the coagulation cascade. We tested the hypothesis that LIF would enhance TF expression in human monocyte-derived macrophages (MDMs). Human peripheral blood mononuclear cells separated from whole blood by density centrifugation were allowed to differentiate into MDMs in primary culture, and were then exposed to LIF, IL-6 and oncostatin M (OSM) for 24 h. LIF and IL-6 receptors, and gp130 were demonstrated in MDMs by immunocytochemistry and RT-PCR. TF procoagulant activity (TF-PCA) was measured by recalcification clotting time and TF protein by Western blotting. The results show that both TF procoagulant activity and TF protein increased significantly in response to LIF over the concentration range of 1-100 nM (P < 0.03). Although OSM and IL-6 tended to enhance TF expression by MDMs, the increase did not reach statistical significance. Anti-LIF receptor and anti-gp130 antibodies attenuated the effect of LIF on TF expression as assayed by both bioassay and flow-cytometry. In conclusion, LIF increases TF-PCA and TF protein in MDMs, and specific anti-LIF receptor antibodies attenuate this effect. Thus, LIF may regulate by a gp130-dependent pathway macrophage-mediated procoagulant function in diverse pathological states involving inflammation and thrombosis and seems to serve as an important mediator at the interface between these processes.

Antigens, CD↗
PubMed1999

Antisense oligonucleotides to stromelysin mRNA inhibit injury-induced proliferation of arterial smooth muscle cells.

Smooth muscle cell migration and proliferation are important events in the formation of intimal lesions associated with atherosclerosis and restenosis following balloon angioplasty. To make this possible, the smooth muscle cell has to change from a contractile to an activated repair cell with capacity to synthesize DNA and extracellular matrix components. There is now considerable evidence that the extracellular matrix has important functions in modulating the phenotypic properties of smooth muscle cells, but less is known about the role of the matrix metalloproteinases. The present study investigates the role of stromelysin in the modulation of rat aortic smooth muscle cell morphology and function following mechanical injury in vitro and in vivo. Antisense mRNA oligonucleotides were used to investigate the role of stromelysin expression in injury-induced phenotypic modulation and the subsequent migration and proliferation of vascular smooth muscle cells. Cultured rat aortic smooth muscle cells and balloon-injured rat carotid arteries were used as experimental models. Light- and electron microscopy were used to follow changes in smooth muscle cell phenotype and lesion formation and incorporation of 3H-thymidine to detect DNA synthesis. Injury-induced DNA synthesis and migration in vitro were inhibited by 72% and 36%, respectively, by adding stromelysin antisense oligonucleotides to the medium prior to injury. In primary cultures, 67% of the smooth muscle cells treated with stromelysin antisense were retained in a contractile phenotype as judged by analysis of cell fine structure, compared to 15% untreated cells and 40% in cells treated with mismatched oligonucleotides. Examination of the carotid arteries one week after balloon injury likewise demonstrated a larger fraction of contractile cells in the inner parts of the media in vessels treated with antisense oligonucleotides compared to those treated with mismatched oligonucleotides. The neointima was also distinctly thinner in antisense-treated than in mismatched-treated and control arteries at this time. These findings indicate that stromelysin mRNA antisense oligonucleotides inhibited phenotypic modulation of rat arterial smooth muscle cells and so caused a decrease in migration and proliferation and neointima formation in response to vessel wall injury.

Animals↗
PubMed1999

Phosphatase activity in the arterial wall after balloon injury: effect of somatostatin analog octreotide.

Phosphorylation of transcription factors fos/jun dimer activator protein (AP)-1 and nuclear factor-kappaB (NF-kappaB) plays a cardinal role in vascular smooth muscle cell (SMC) response to growth stimuli. Activity of protein tyrosine (PTP) and serine/threonine phosphatases (PP2A, B, and C) regulates in balance with the activity of protein kinases the level of transcription factor phosphorylation. Somatostatin analog octreotide stimulates phosphatase activity and inhibits cell growth. We examined in rats the activity of tissue phosphatases after arterial wall injury and treatment with octreotide and its effect on AP-1 and NF-kappaB phosphorylation and arterial response to injury. The activity of PTP did not change after balloon injury. Treatment of rats with PTP stimulator octreotide increased the PTP activity by 20% +/- 18% in uninjured arteries (p = 0.04 compared with control) and by 49% +/- 44% compared with injured untreated rats (p = 0.017). Treatment of rats with okadaic acid, a specific phosphatase inhibitor, prevented the octreotide-induced increase in PTP activity. PP2A activity of uninjured arteries was not affected significantly with treatment with octreotide (105% +/- 21%, p = 0.57 compared with control). After balloon injury PP2A activity was significantly reduced, 54% +/- 24% of control (p = 0.001). This reduction was prevented with treatment with octreotide, activity 88% +/- 25% of control. When rats were treated with octreotide and okadaic acid, the activity of PP2A in uninjured arteries was decreased to 65% +/- 12% of control (p = 0.03) and the injury-induced reduction was preserved, activity 54% +/- 8% of control (p = 0.001). There was no change in PP2B and C activity after balloon injury. Increased phosphatase activity with octreotide was associated with stabilization of the unphosphorylated form and reduction in nuclear binding of AP-1 and NF-kappaB and was associated with reduced SMC proliferation after balloon injury. Inhibition of increased phosphatase activity with okadaic acid was associated with increased nuclear binding of AP-1 and NF-kappaB. Increased nuclear binding of AP-1 and NF-kappaB after injury was associated with increased expression of fos, jun, and p105 subunit mRNA and restored the proliferative response of SMC after balloon injury. We conclude that the activity of PP2A is decreased after arterial balloon injury which leads to increased AP-1 and NF-kappaB phosphorylation and nuclear binding and is involved in regulation of SMC proliferation. Treatment with octreotide prevented the injury-induced reduction in PP2A activity and decreased transcription factor phosphorylation and SMC proliferation. Modification of phosphatase activity is a potential regulatory mechanism of arterial wall response to injury.

Animals↗
PubMed1998

Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: We previously reported marked inhibitory effects of recombinant apolipoprotein (apo) A-I(Milano)/phospholipid complex (A-I[Milano]/PC) on neointimal lesions in balloon-injured iliofemoral arteries of hypercholesterolemic rabbits. In this study, we tested the hypothesis that apo A-I(Milano)/PC would inhibit aortic atherosclerosis in apo E-deficient mice. METHODS AND RESULTS: Thirty-five apo E-deficient mice fed a high-cholesterol diet were included in the study. Control mice were killed at 20 (n=8) or 25 (n=7) weeks. Treated mice received 18 injections of either 40 mg/kg apo A-I(Milano)/PC (n=15) or PC only (n=5) intravenously every other day from 20 weeks until death at 25 weeks. Aortic atherosclerosis was identified with Sudan IV staining. Lipid and macrophage contents of the aortic sinus plaques were measured after oil-red O and Mac-1 antibody staining, respectively, and quantified with computed morphometry. In control mice, from 20 to 25 weeks, aortic atherosclerosis increased by 59% (11 +/- 1% versus 17 +/- 5% of the aortic surface, P=.002), and lipid content increased by 45% (22 +/- 8% versus 32 +/- 6% of plaque area, P=.02) without a significant change in macrophage content (10.8 +/- 2% versus 13.2 +/- 6%). Compared with 20-week-old untreated control mice, PC only-treated mice at 25 weeks demonstrated a 32% increase in aortic atherosclerosis (11 +/- 1% versus 15 +/- 4%, P=.01) and an increase in lipid content (22 +/- 8% versus 47 +/- 3%, P<.0001) without a change in macrophage content (10.8 +/- 2% versus 11 +/- 2%). In comparison with 20-week-old untreated control mice, 25-week-old apo A-I(Milano)/PC-treated mice demonstrated no increase in aortic atherosclerosis (11 +/- 1% versus 10 +/- 4%, P=NS), a 40% reduction in lipid content (22 +/- 8% versus 13 +/- 8%, P=.01), and a 46% reduction in macrophage content (10.8 +/- 2% versus 5.8 +/- 2.9%; P=.03). Serum cholesterol levels were markedly elevated in all groups and did not change significantly with apo A-I(Milano)/PC or PC only. In vitro, apo A-I(Milano)/PC stimulated cholesterol efflux from cholesterol-loaded FU5AH hepatoma cell lines in a dose-dependent manner, whereas PC only or PC-free apo A-I(Miano) had no effect. CONCLUSIONS: Recombinant A-I(Milano)/PC prevented progression of aortic atherosclerosis and reduced lipid and macrophage content of plaques in apo E-deficient mice despite severe hypercholesterolemia. Thus, A-I(Milano)/PC may have a role in inhibiting progression and promoting stabilization of atherosclerosis.

Animals↗
PubMed1998

Lipoprotein-like phospholipid particles inhibit the smooth muscle cell cytotoxicity of lysophosphatidylcholine and platelet-activating factor.

Oxidation of LDL is associated with degradation of phosphatidylcholine into platelet-activating factor (PAF)-like phospholipids and lysophosphatidylcholine (LPC). Exposure of cultured human smooth muscle cells to PAF and LPC in a concentration of 25 micromol/L was found to result in complete cell death, as assessed by the MTT cytotoxicity assay and cell counting. Addition of 50 microg/mL apolipoprotein A-I- and apolipoprotein A-I(Milano)-containing phospholipid particles completely inhibited this cytotoxicity. Phospholipid complexes alone were almost as effective, whereas free apolipoprotein A-I(Milano) and albumin were without effect, suggesting that the effect was phospholipid dependent. Experiments using [14C]LPC demonstrated that apolipoprotein A-I- and apolipoprotein A-I(Milano)-containing phospholipid particles effectively bind LPC. The results show that HDL-like phospholipid particles effectively inhibit the toxic effect of phospholipids and other lipid-soluble factors. The ability of HDL to inhibit the proinflammatory and toxic effects of phospholipids generated during oxidation of LDL may be responsible for part of the antiatherogenic properties of HDL.

Apolipoprotein A-I↗
PubMed1998

An animal model to study local oxidation of LDL and its biological effects in the arterial wall.

Oxidized LDL (oxLDL) is present in atherosclerotic lesions and is believed to play a key role in atherogenesis. Mainly on the basis of cell culture studies, oxLDL has been shown to produce many biological effects that influence the atherosclerotic process. To study LDL oxidation in vivo, we have established a model in which Sprague-Dawley rats are given a single injection of unmodified human LDL (> or = 4 mg/kg body weight). Within 6 hours, an accumulation of apolipoprotein B and epitopes present on oxLDL are detected in the arterial endothelium and media. The presence of oxLDL is associated with activation of the transcription factor nuclear factor-kappaB in the endothelium as well as endothelial expression of intercellular adhesion molecule-1. Injection of LDL enriched with the antioxidant probucol resulted in arterial accumulation of apolipoprotein B, but the expression of oxLDL-specific epitopes was reduced at 24 hours. Thus, this simple model has the potential to analyze the mechanisms behind and biological effects of LDL oxidation in vivo.

Adult↗
PubMed1998

Therapeutic Concentrations of Heparin Augment Platelet Activation at the Time of Coronary Angiography.

Background: Besides its anticoagulant effects, heparin is known to alter platelet (PLT) function. We examined the effects of unfractionated heparin on PLT function in patients with stable coronary artery disease (CAD). Methods and Results: PLT function was evaluated by whole-blood flow cytometry to detect PLT CD62 expression and by impedance aggregometry to assess the platelet aggregation (PA) before and after bolus intravenous administration of low-dose heparin (2713 +/- 1231 U) in 16 patients undergoing coronary angiography (group 1) and high-dose heparin (7937 +/- 2414 U) in 16 patients undergoing coronary angioplasty (group 2). Activated clotting time (ACT) and plasma antifactor-Xa heparin levels also were measured. Heparin increased PLT CD62 expression, which was significantly more pronounced in group 1 patients with plasma heparin levels less than 0.7 U/mL and ACT of 222 +/- 52 seconds compared with group 2 patients with heparin levels greater than 0.7 U/mL and ACT of 365 +/- 86 seconds (8 +/- 9 v -1 +/- 4% change in resulting PLTs, P =.01, and 11 +/- 12 v 1 +/- 6% increase in adenosine diphosphate (ADP) [5 µM]-stimulated PLTs, P =.02). Heparin produced a slight increase in PA in group 1 patients (1.4 +/- 5.3 ohms) as compared with the group 2 patients, where it significantly suppressed PA (-3.0 +/- 5.3 ohms, P.05 v group 1). A strong and statistically significant negative correlation between change in platelet CD62 expression and heparin concentration was observed in group 1 patients (r = -.5, P =.05, -ADP; r = -.65, P =.006, +ADP), whereas this relationship was weak and did not reach statistical significance in group 2 patients (r = -0.4, P =.2, -ADP; r =.11, P = 0.9; +ADP). Conclusion: Bolus administration of intravenous heparin augmented PLT activation in patients at clinically relevant anticoagulant concentrations (<0.7 U/mL). These findings may have implications for optimal dosing strategy for heparin as an antithrombotic agent in clinical situations characterized by platelet-dependent thrombotic events.

Journal Article↗
PubMed1998

Mass-sensing, multianalyte microarray immunoassay with imaging detection.

Miniaturization of ligand binding assays may reduce costs by decreasing reagent consumption, but it is less apparent that miniaturized assays can simultaneously exceed the sensitivity of macroscopic techniques by analyte "harvesting" to exploit the total analyte mass available in a sample. Capture reagents (avidin or antibodies) immobilized in 200-microm diameter zones are shown to substantially deplete analyte from a liquid sample during a 1-3-h incubation, and the assays that result sense the total analyte mass in a sample rather than its concentration. Detection of as few as 10(5) molecules of analyte per zone is possible by fluorescence imaging in situ on the solid phase using a near-infrared dye label. Single and multianalyte mass-sensing sandwich array assays of the IgG subclasses show the sensitivity and specificity of ELISA methods but use less than 1/100 the capture antibody required by the 96-well plate format.

Avidin↗
PubMed1997

Nuclear factor-kappaB activity and arterial response to balloon injury.

We studied the effect of arterial balloon injury on nuclear factor-kappaB (NF-kappaB) mobilization and ICAM-1 expression in untreated rats and rats treated with aspirin. Baseline NF-kappaB nuclear binding in smooth muscle cells (SMC) increased two-fold within 6 h after balloon injury. The binding returned to baseline 3 days after injury. Consistently nuclear staining of p65 active subunit increased in the medial SMC following balloon injury. There was no baseline ICAM-1 expression. Within 3 days after balloon injury there was marked medial ICAM-1 expression, that localized to neointima 7 days after injury and to regrowing endothelial cells 14 days after injury. Treatment with aspirin inhibited NF-kappaB nuclear translocation and binding and was associated with reduction of ICAM-1 expression, SMC proliferation and neointimal thickening following balloon injury. These data suggest that transient mobilization of NF-kappaB in vascular SMC after balloon injury mediates ICAM-1 expression and is involved in arterial response to balloon injury.

Animals↗
PubMed1997

Dissolution of thrombotic arterial occlusion by high intensity, low frequency ultrasound and dodecafluoropentane emulsion: an in vitro and in vivo study.

OBJECTIVES: We examined the effectiveness of the microbubbles of an echo contrast agent, dodecafluoropentane (DDFP) emulsion, to enhance low frequency ultrasound clot disruption in vitro and in vivo. BACKGROUND: Ultrasound is reported to facilitate clot dissolution, and microbubbles could theoretically enhance ultrasound clot dissolution by augmenting cavitational effects. METHODS IN VITRO STUDIES: The disruption rate of fresh human clots by ultrasound (24 kHz, 2.9 W/cm2) was examined in saline and DDFP emulsion. In vivo studies: Using a rabbit iliofemoral thrombotic occlusion model, recanalization rate and histopathologic findings were compared among groups treated with DDFP emulsion alone, transcutaneous ultrasound (20 kHz, 1.5 W/cm2) alone and with DDFP emulsion and ultrasound combined. RESULTS: The ultrasound clot disruption rate was significantly (p < 0.01) increased, from 72 +/- 18% (mean +/- SD) in saline to 98 +/- 4% in DDFP emulsion in 3 min in vitro. No vessel was recanalized by DDFP emulsion alone (0%), and only a single artery was patent after ultrasound treatment alone (9%). In contrast, 82% of iliofemoral arteries were angiographically recanalized after ultrasound treatment with DDFP emulsion. Histologically, the patent arteries had only minimal focal mural thrombus, with no evidence of vessel wall damage. However, substantial damage was observed in rabbit dermis and subcutaneous tissue. CONCLUSIONS: 1) DDFP emulsion, an echo contrast agent, significantly enhances the clot-disrupting effect of low frequency ultrasound in vitro and in an in vivo rabbit iliofemoral occlusion model. 2) This simple combination therapy has potential for clinical application in patients with thrombotic arterial occlusions.

Animals↗
PubMed1997

Immunization with homologous oxidized low density lipoprotein reduces neointimal formation after balloon injury in hypercholesterolemic rabbits.

OBJECTIVES: In this study we tested the hypothesis that immunization with homologous oxidized low density lipoprotein (oxLDL) would inhibit the neointimal response to balloon injury in hypercholesterolemic rabbits. BACKGROUND: Immunization with homologous oxLDL has been shown to markedly reduce aortic atherosclerosis in LDL receptor-deficient as well as cholesterol-fed rabbits; however, the effect of this strategy on the balloon injury-induced neointimal lesion is unknown. METHODS: New Zealand White rabbits were immunized with 280 microg of homologous native LDL (n = 5), copper-oxidized LDL (n = 5) or phosphate buffer as control (n = 5) and fed a 1% cholesterol diet. Rabbits were reimmunized after 3 weeks, and balloon injury of the right ileofemoral artery was performed 1 week later. Four weeks after balloon injury, rabbits were killed, and the neointimal lesion area was measured by computerized morphometry after perfusion fixation of the arteries. Circulating antibodies against oxLDL were measured by enzyme-linked immunosorbent assay. RESULTS: In comparison with the control animals, those immunized with oxLDL had a 58% reduction in the neointimal area (0.53 +/- 0.13 vs. 1.27 +/- 0.26 mm2; p = 0.01). The group immunized with native LDL had a 19% reduction in the neointimal area compared with the control group (p = NS). Circulating cholesterol levels and antibody titers against oxLDL were comparable in the three groups. There was a trend toward reduced immunoreactivity for T cells and oxLDL in the neointima of oxLDL-immunized animals. CONCLUSIONS: Hypercholesterolemic rabbits immunized with homologous oxLDL have a markedly reduced neointimal area after balloon injury despite severe hypercholesterolemia. Together with previous work, these data suggest that an immunization strategy (vaccination) against atherosclerosis and restenosis warrants further investigation.

Animals↗
PubMed1997

Local Delivery of an Ultra-short-acting Nitric Oxide-releasing Compound, DMHD/NO, Is Highly Effective in Inhibiting Acute Platelet-Thrombus Formation on Injured Arterial Strips.

BACKGROUND: Nitric oxide (NO) plays an important role in modulating platelet-vessel wall interaction following vascular injury. We exampled the effects of local infusion of an ultra-short-acting NO-releasing compound: NO adduct of N, N'-dimethylhexanediamine (DMHD/NO), sodium nitroprusside, intravenous nitroglycerin, and aspirin on acute platelet-thrombus formation under conditions of high-shear blood flow in a rabbit extracorporeal perfusion model. MATERIALS AND METHODS: Strips of porcine aortic media were perfused in a Badimon chamber with arterial blood from 20 New Zealand White rabbits for 10 minutes at a shear rate of 1700 s(-1). Thrombus formation was quantified by morphometric analysis of thrombus area. Effects on collagen-induced platelet aggregation, blood pressure, bleeding time, and activated clotting time were also examined. RESULTS: DMHD/NO inhibited thrombus area and platelet aggregation in a dose-dependent manner with a 90% reduction in thrombus area (0.018 +/- 0.039 vs 0.215 +/- 0.085 mm(2)/mm control, P <.001) and a 50% reduction in platelet aggregation (4.8 +/- 4.4 vs 9.9 +/- 4.1 Omicron control, P =.04) at the highest dose of 1.0 nM/kg and 100 µM/L, respectively, without any effects on blood pressure, bleeding time, or activated clotting time. In contrast, equimolar concentrations of sodium nitroprusside and intravenous nitroglycerin had significantly reduced effects on thrombus area compared to DMHD/NO and were associated with significant reductions in blood pressure and prolongation of bleeding time. Aspirin had no effect on thrombus area at 1 µM/kg but reduced thrombus area and prolonged bleeding time at 2 and 5 µM/kg. CONCLUSIONS: Local delivery of DMHD/NO produced a 90% inhibition of experimental acute platelet-thrombosis under high-shear flow conditions without producing adverse systemic hemodynamic or hemostatic effects. Thus, inhibition of thrombus formation by local delivery of a rapidly acting NO donor may be an effective strategy for prevention of arterial injury-induced thrombosis.

Journal Article↗
PubMed1997

Direct effects of somatostatin analog octreotide on insulin-like growth factor-I in the arterial wall.

Local vascular expression and action of insulin-like growth factor-I (IGF-I) appear to be important in the biologic events that follow arterial wall injury. Octreotide, a long-acting somatostatin analog, is a potent inhibitor of the growth hormone/IGF-I axis. We examined the effects of octreotide on the vascular IGF-I and IGF-binding proteins (IGFBP), gene regulation, smooth muscle cell proliferation, and neointimal thickening after arterial wall injury. Treatment with octreotide selectively decreased IGF-I mRNA expression in normal rat arteries by 70% and prevented the induction of the IGF-I gene after balloon injury. Because up-regulation of platelet-derived growth factor-A gene was not affected, and because there was no change in plasma growth hormone, IGF-I, and glucagon levels, it appears that this effect is selective and mediated locally. Of the IGFBP, IGFBP-4 was modestly up-regulated after balloon injury, whereas treatment with octreotide had no effect on IGFBP-4 expression. The inhibitory effects of octreotide on vascular IGF-I were associated with a decrease in the number of proliferating cell nuclear antigen-positive cells and an up to 90% reduction in neointimal thickening after balloon injury in a dose-dependent fashion.

Angioplasty, Balloon↗
PubMed1996

Transcutaneous ultrasound augments lysis of arterial thrombi in vivo.

BACKGROUND: External ultrasound has a synergistic effect on thrombus disruption with thrombolytic agents in vitro. We hypothesized that transcutaneous ultrasound could augment thrombolysis in vivo. METHOD AND RESULTS: Thrombus formation was induced electrically in 48 pairs of iliofemoral arteries of 24 rabbits; arterial occlusions were documented angiographically. In 17 of 24 rabbits, 25000 units/kg streptokinase was then administered intravenously. The pairs of iliofemoral arteries were randomized to receive ultrasound treatment or no ultrasound treatment. Low-frequency (26 kHz) ultrasound (continuous wave, 18 W/cm2) was applied transcutaneously over the area of occlusion. In 7 of 24 rabbits, 14 thrombotically occluded iliofemoral arteries were exposed to ultrasound alone without streptokinase. The results were evaluated through the use of angiography (TIMI grade flow) and histopathology. After 30 +/- 10 minutes of activated sonication combined with intravenous streptokinase, 10 of 17 iliofemoral arteries (59%) treated with transcutaneous ultrasound were widely patent angiographically, with TIMI grade 3 flow. Histologically, the patent arteries had only minimal focal moral thrombus. The angiographic patency rate was significantly lower in the control groups: 1 of 17 arteries (6%) treated with streptokinase alone (P = .0012) and 1 of 14 arteries (7%) treated with ultrasound alone (P = .0036). CONCLUSIONS: In vivo transcutaneous ultrasound significantly augments lysis of thrombi with streptokinase in rabbit iliofemoral arteries.

Angiography↗