The effect of L-arginine or L-citrulline supplementation on biochemical parameters and the vascular aortic wall in high-fat and high-cholesterol-fed rats.

The aim of the present study is to investigate the potential role of L-arginine or L-citrulline in rats fed high-fat and high-cholesterol (HFC) diet. HFC feeding increased significantly serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, urea and all lipid profiles and decreased significantly serum high-density lipoprotein-cholesterol (HDL-c) and non significantly serum nitric oxide levels. L-arginine or L-citrulline administration reversed the increase in serum AST and ALT activities, urea and all lipid profiles. These effects were associated with a concomitant increase in HDL-c and nitric oxide levels. In general, rats fed HFC diet and orally treated with L-arginine or L-citrulline had higher relative percentage of 18:0, 20:0 and 22:6 and lower 16:0 fatty acids than rats fed HFC diet. Light and transmission electron microscopic findings of the thoracic aorta confirmed the biochemical results and demonstrated structural changes in the endothelial cells of the intimal layer, medial smooth muscle cells as well as in the adventitial layer in HFC fed-animals. However, these findings indicate little structural alterations in animals supplemented with L-arginine or L-citrulline along with HFC feeding. In the present study, L-arginine or L-citrulline was effective hypocholesterolemic and hypolipidemic agents in rats.

Efecto del sulodexide sobre la capacidad de relajación y alteraciones estructurales de la arteria aorta en ratas diabéticas por estreptozotocina / Effect of sulodexide on aortic vasodilation capacity and associated morphological changes in rats with streptozotocin-induced diabetes

La disfunción endotelial (DE) se presenta en pacientes con hipercolesterolemia, hipertensión arterial, obesidad y diabetes mellitus. Evidencias sugieren un papel de los glicosaminoglicanos en la DE. Evaluamos el efecto del sulodexide (SLD), un glicosaminoglicano utilizado en el tratamiento de la albuminuria y la enfermedad isquémica en pacientes diabéticos, sobre la relajación arterial y los cambios morfológicos en un modelo experimental de diabetes tipo 1. La diabetes se indujo a ratas Sprague Dawley administrando estreptozotocina (STZ), 60 mg/kg, i.v. Los animales fueron distribuidos en los siguientes grupos: I= control, II= diabéticas, III: control + sulodexide, IV= diabéticas + sulodexide (15 mg/kg/día s.c). A los 3 meses fueron sacrificados, las aortas extraídas para evaluar la relajación vascular inducida por acetilcolina (Ach) y nitroprusiato de sodio en anillos precontraídos con fenilefrina. Fueron evaluadas histológicamente mediante microscopía de luz y coloraciones diversas. El SLD in vitro no modificó la tensión basal de los anillos arteriales en reposo o precontraídos con fenilefrina. La diabetes disminuyó la capacidad de relajación arterial en respuesta a la Ach en un 28,8-35,1% vs control, efecto que fue prevenido por SLD. No se observó diferencia significativa en la relajación inducida por nitroprusiato sódico entre los grupos. El estudio histológico en los animales diabéticos mostró alteraciones estructurales, particularmente en la íntima y la adventicia, cambios que fueron prevenidos por el tratamiento con SLD. Nuestros resultados apoyan la potencial utilidad terapéutica del SLD en el tratamiento de la disfunción endotelial.

Endothelial dysfunction (ED) is observed in patients with hypercholesterolemia, arterial hypertension, obesity and diabetes mellitus. Recent evidences suggest the involvement of glycosaminoglycans(GSG) in ED. We evaluated the effect of sulodexide (SLD), a natural GSG used in albuminuria and ischemic diabetes treatment, on arterial relaxation and vascular morphological changes in a diabetic type I model. Diabetes was induced, in Sprague-Dawley rats by streptozotocine (STZ) administration, 60 mg, iv. Rats were divided into four groups; I: control, II: diabetics, III: control + SLD, IV: diabetics treated with SLD (15 mg/day). After three months, phenylephrine precontracted aortic rings were used to evaluate acetylcholine (ACh) and sodium nitroprusside (NPS) relaxation capacities. Light microscopy of aorta was done with several staining procedures. In vitro, SLD did not change smooth muscle tone in resting or phenylephrine precontracted aortic rings. In diabetic rats, ACh relaxation was 28.8-35.1% lower than in control rats. Diabetic rats treated with SLD showed aortic ACh relaxation similar to control rats. No significative statistical difference was found in endothelium-independent NPS relaxation, between the different groups. Light microscopy histological studies revealed important morphological alterations, particularly in intima and adventitia layers of aortic artery; those changes were dramatically reversed in SLD treated rats. Our experiments support the conclusion that SLD is a potential drug for improving endothelial dysfunction in diabetes.

[Effect of sulodexide on aortic vasodilation capacity and associated morphological changes in rats with streptozotocin-induced diabetes]. / Efecto del sulodexide sobre la capacidad de relajación y alteraciones estructurales de la arteria aorta en ratas diabéticas por estreptozotocina.

Endothelial dysfunction (ED) is observed in patients with hypercholesterolemia, arterial hypertension, obesity and diabetes mellitus. Recent evidences suggest the involvement of glycosaminoglycans (GSG) in ED. We evaluated the effect of sulodexide (SLD), a natural GSG used in albuminuria and ischemic diabetes treatment, on arterial relaxation and vascular morphological changes in a diabetic type I model. Diabetes was induced, in Sprague-Dawley rats by streptozotocine (STZ) administration, 60 mg, i.v. Rats were divided into four groups; I: control, II: diabetics, III: control + SLD, IV: diabetics treated with SLD (15 mg/day). After three months, phenylephrine precontracted aortic rings were used to evaluate acetylcholine (ACh) and sodium nitroprusside (NPS) relaxation capacities. Light microscopy of aorta was done with several staining procedures. In vitro, SLD did not change smooth muscle tone in resting or phenylephrine precontracted aortic rings. In diabetic rats, ACh relaxation was 28.8-35.1% lower than in control rats. Diabetic rats treated with SLD showed aortic ACh relaxation similar to control rats. No significative statistical difference was found in endothelium-independent NPS relaxation, between the different groups. Light microscopy histological studies revealed important morphological alterations, particularly in intima and adventitia layers of aortic artery; those changes were dramatically reversed in SLD treated rats. Our experiments support the conclusion that SLD is a potential drug for improving endothelial dysfunction in diabetes.

Fresh soy oil protects against vascular changes in an estrogen-deficient rat model: an electron microscopy study.

OBJECTIVE: To observe the effects of consuming repeatedly heated soy oil on the aortic tissues of estrogen-deficient rats. METHODS: Thirty female Sprague Dawley rats (200-250 g) were divided equally into five groups. One group served as the normal control (NC) group. The four treated groups were ovariectomized and were fed as follows: 2% cholesterol diet (OVXC); 2% cholesterol diet + fresh soy oil (FSO); 2% cholesterol diet + once-heated soy oil (1HSO); and 2% cholesterol diet + five-times-heated soy oil (5HSO). After four months, the rats were sacrificed, and the aortic tissues were obtained for histological studies. RESULTS: After four months of feeding, the NC, FSO and 1HSO groups had a lower body weight gain compared to the OVXC and 5HSO groups. The tunica intima/media ratio in the 5HSO group was significantly thicker (p < 0.05) compared to the NC, OVXC and FSO groups. Electron microscopy showed that endothelial cells were normally shaped in the FSO and NC groups but irregular in the 1HSO and 5HSO groups. A greater number of collagen fibers and vacuoles were observed in the 5HSO group compared to the other treatment groups. CONCLUSIONS: Fresh soy oil offered protection in the estrogen-deficient state, as these rats had similar features to those of the NC group. The damage to the tunica intima and the increase in the ratio of tunica intima/media thickness showed the deleterious effect of consuming repeatedly heated soy oil in castrated female rats.

Fresh soy oil protects against vascular changes in an estrogen-deficient rat model: an electron microscopy study

OBJECTIVE: To observe the effects of consuming repeatedly heated soy oil on the aortic tissues of estrogen-deficient rats. METHODS: Thirty female Sprague Dawley rats (200- 250 g) were divided equally into five groups. One group served as the normal control (NC) group. The four treated groups were ovariectomized and were fed as follows: 2 percent cholesterol diet (OVXC); 2 percent cholesterol diet + fresh soy oil (FSO); 2 percent cholesterol diet + once-heated soy oil (1HSO); and 2 percent cholesterol diet + five-times-heated soy oil (5HSO). After four months, the rats were sacrificed, and the aortic tissues were obtained for histological studies. RESULTS: After four months of feeding, the NC, FSO and 1HSO groups had a lower body weight gain compared to the OVXC and 5HSO groups. The tunica intima/media ratio in the 5HSO group was significantly thicker (p < 0.05) compared to the NC, OVXC and FSO groups. Electron microscopy showed that endothelial cells were normally shaped in the FSO and NC groups but irregular in the 1HSO and 5HSO groups. A greater number of collagen fibers and vacuoles were observed in the 5HSO group compared to the other treatment groups. CONCLUSIONS: Fresh soy oil offered protection in the estrogen-deficient state, as these rats had similar features to those of the NC group. The damage to the tunica intima and the increase in the ratio of tunica intima/media thickness showed the deleterious effect of consuming repeatedly heated soy oil in castrated female rats.

A detailed microscopic study of the changes in the aorta of experimental model of postmenopausal rats fed with repeatedly heated palm oil.

Hypercholesterolaemia, increase in lipid peroxidation and hyperhomocysteinaemia may contribute to the pathogenesis of atherosclerosis. This study was performed to examine the effects of repeatedly heated palm oil mixed with 2% cholesterol diet on atherosclerosis in oestrogen-deficient postmenopausal rats. Ovariectomy causes disruption of tunica intima layer of the rat aorta simulating a postmenopausal condition in females. Twenty-four ovariectomized female Sprague-Dawley rats were divided into four groups. The control group received 2% cholesterol diet without palm oil. A diet with 2% cholesterol content fortified with fresh, once-heated and five-times-heated palm oil was given to the other treatment groups. The rats were sacrificed at the end of 4 months of study and the aortic arch tissue was processed for histomorphometry and electron microscopy. On observation, there was disruption of the intimal layer of the ovariectomized rat aorta. There was no obvious ultrastructural change in the aorta of the rats fed with fresh palm oil. The ultrastructural changes were minimal with once-heated palm oil, in which there was a focal disruption of the endothelial layer. The focal disruption was more pronounced with five-times-heated palm oil. The results of this study show that the ingestion of fresh palm oil may have a protective effect on the aorta but such a protective action may be lost when the palm oil is repeatedly heated. The study may be clinically important for all postmenopausal women who are susceptible to atherosclerosis.

Focal arterial inflammation is augmented in mice with a deficiency of the protein C gene.

Increased risk of thrombosis, with propitious conditions for fibrin deposition, along with upregulation of inflammation, are important factors that enhance plaque formation in atherosclerosis. Evidence supporting the role of anticoagulant protein C (PC) as an inflammatory agent has emerged, supplementing its well-known function as an anticoagulant. Thus, we sought to examine whether a PC deficiency would lead to an enhanced response to an acute arterial hyperplasic challenge. The presentation of early arterial inflammation was studied using a copper/silicone arterial cuff model of accelerated focal neointimal remodeling in mice with a heterozygous total deficiency of PC (PC+/-). Increased inflammation, cell proliferation, cell migration, fibrin elevation, and tissue necrosis were observed in the treated arteries of PC+/- mice, as compared to arteries of equally challenged age- and gender-matched WT mice. These results indicate that PC+/- mice subjected to this challenge displayed enhanced focal arterial inflammation and thrombosis, leading to larger neointimas and subsequent localized occlusion, as compared to their WT counterparts.

Effect of D-003 on intimal thickening and circulating endothelial cells in rabbit cuffed carotid artery.

D-003 is a mixture of very-high-molecular-weight aliphatic primary acids purified from sugar-cane (Saccharum officinarum L.) wax, in which octacosanoic acid is the most abundant component. Previous experimental studies have shown that D-003 not only shows cholesterol-lowering and anti-platelet effects, but also reduces thromboxane B2 and increases prostacyclin levels. It acts by inhibiting cholesterol biosynthesis. The positioning of a non-occlusive silicone collar around the rabbit carotid artery results in the formation of a neointima. Collars were placed around the left carotid for 15 days. The contralateral artery was sham-operated. We included three experimental groups: A control group received vehicle, and two others received D-003 at 5 and 25 mg/kg until sacrificed. Samples of arteries were examined by light microscopy. To evaluate intimal thickening the cross-sectional areas of intima and media were measured. Neointima was significantly reduced in D-003-treated animals compared with controls. Furthermore, the circulating endothelial cell has been studied in this experimental model with endothelium damage. The results demonstrate the protective effect of D-003 on vascular endothelium of the studied rabbits. It is concluded that the protective effect of D-003 against neointima formation and circulating endothelial cells in this experimental model could represent potential beneficial pleiotropic effects in the anti-atherogenic profile of this substance, beyond its cholesterol-lowering and anti-platelet effects independently demonstrated.

S18886, a selective TP receptor antagonist, inhibits development of atherosclerosis in rabbits.

OBJECTIVE: To investigate the effect of S18886, a novel TP (thromboxane A2 and prostaglandin endoperoxide) receptor antagonist, on the development of aortic fatty streaks and advanced lesions in a rabbit model of atherosclerosis and restenosis. METHODS AND RESULTS: The right iliac artery of 96 rabbits (8 groups, n=12/group) was balloon injured, then the animals were fed a cholesterol-enriched diet for 6 weeks. In Groups 1-4, concomitant oral administration of S18886 at 5 mg/kg/day over the 6-week-period reduced the intima to media ratio of lesions in the uninjured aorta and injured iliac artery, the accumulation of macrophages and the expression of ICAM-1 compared with 1 mg/kg/day S18886, 30 mg/kg/day aspirin and placebo, with no effect on body weight or plasma cholesterol levels. In Groups 5-8, 2 weeks of treatment with 5 mg/kg/day S18886 reduced the intima to media ratio of restenosing lesions when pre-formed iliac artery lesions underwent a second balloon injury at week 6. The smaller lesions resulting from S18886 treatment correlated with a significant decrease in the neointimal area occupied by macrophages, as well as in ICAM-1 expression, with no effect on the smooth muscle component. Aspirin treatment had no significant effect on the neointimal smooth muscle component, but partially inhibited macrophage infiltration, without inhibiting ICAM-1 expression. CONCLUSION: Inhibition of the TP receptor using S18886 causes a significant decrease in the recruitment of monocyte/macrophages within fatty streaks in the uninjured aorta and within primary and restenosing atherosclerotic lesions in the iliac artery of rabbits. Since TP receptor agonists, such as thromboxane A2, prostanoid endoperoxides and isoprostanes participate in vessel wall inflammation and are localized and increased in atherosclerotic plaques, treatment with S18886 may enhance atherosclerotic lesion stability by attenuating inflammatory processes that ultimately lead to plaque rupture.

Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis.

BACKGROUND: Drug-eluting stents have shown promising antirestenotic effects in clinical trials. Non-stent-based local delivery of antiproliferative drugs may offer additional flexibility and also reach vessel areas beyond the immediate stent coverage. The aim of the present study was to evaluate a novel method of local drug delivery based on angioplasty balloons. METHODS AND RESULTS: Stainless steel stents (n=40; diameter, 3.0 to 3.5 mm; length, 18 mm) were implanted in the left anterior descending and circumflex coronary arteries of domestic pigs. Both conventional uncoated and 3 different types of paclitaxel-coated, percutaneous transluminal coronary angioplasty balloons (contact with vessel wall for 1 minute) were used. No difference in short-term tolerance between coated and uncoated balloons and no signs of thrombotic events were observed. Quantitative angiography and histomorphometry of the stented arteries asserted the statistical equality of the baseline parameters between the control and the 3 treatment groups. Paclitaxel balloon coating led to a marked, dose-dependent reduction of parameters characterizing in-stent restenosis (reduction of neointimal area up to 63%). Despite the marked reduction in neointimal proliferation, endothelialization of stent struts was present in all samples. There was no evidence of a significant inflammatory response in the neighborhood of the stent struts. CONCLUSIONS: Paclitaxel balloon coating is safe, and it effectively inhibits restenosis after coronary angioplasty with stent implantation in the porcine model. The degree of reduction in neointimal formation was comparable to that achieved with drug-eluting stents.

Effects of long-term daily low-dose supplementation with antioxidant vitamins and minerals on structure and function of large arteries.

OBJECTIVE: Limited data exist from randomized trials evaluating, noninvasively, the impact of antioxidant supplementation on vascular structure and function. METHODS AND RESULTS: This is a substudy of the SU.VI.MAX Study, which is a randomized, double-blind, placebo-controlled, cardiovascular and cancer primary prevention trial. Eligible participants (free of symptomatic chronic diseases and apparently healthy) were randomly allocated to daily receive either a combination of antioxidants (120 mg vitamin C, 30 mg vitamin E, 6 mg beta carotene, 100 microg selenium, and 20 mg zinc) or placebo and followed-up over an average of 7.2+/-0.3 years. At the end-trial examination, the carotid ultrasound examination and carotid-femoral pulse-wave velocity (PWV) measurement were performed blindly in 1162 subjects aged older than 50 years and living in the Paris area. The percentage of subjects with carotid plaques was higher in the intervention group compared with the placebo group (35.2% versus 29.5%, P=0.04). Common carotid intima-media thickness (mean+/-SD) was not different between the 2 groups (0.70+/-0.08 versus 0.70+/-0.08 mm, P=0.38). Mean PWV tended to be lower (indicating less stiff aortic arteries) in the intervention group but the difference did not reach statistical significance (P=0.13). CONCLUSIONS: These results suggest no beneficial effects of long-term daily low-dose supplementation of antioxidant vitamins and minerals on carotid atherosclerosis and arterial stiffness.

Thermal treatment attenuates neointimal thickening with enhanced expression of heat-shock protein 72 and suppression of oxidative stress.

BACKGROUND: The beneficial effects of thermal therapy have been reported in several cardiovascular diseases. However, it is unknown whether the thermal treatment has some beneficial roles against the development of atherosclerosis. METHODS AND RESULTS: The inflammatory arterial lesion was introduced by placement of a polyethylene cuff on femoral arteries of male Sprague-Dawley rats for 4 weeks. Thermal-treated group underwent daily bathing in 41 degrees C hot water for 15 minutes. Neointimal thickening along with immunohistochemical expression of heat-shock proteins (HSPs), monocyte chemoattractant protein-1 (MCP-1), and NADPH oxidase were compared with those of a thermally untreated (Control) group. Morphometric analysis demonstrated a significant suppression of neointimal thickening in thermal-treated group compared with the Control group (intimal/medial area ratios, 0.01+/-0.01 versus 0.31+/-0.04, P<0.01). Expression of MCP-1 and infiltration of ED-positive cells were enhanced in the adventitial layer of Control. More importantly, expression of HSP72 in media was enhanced by thermal treatment. Expression of p22-phox, the major membrane subunit of NADPH oxidase, and MCP-1 was augmented in cuff-injured adventitia of the Control but not the thermal-treated groups. CONCLUSIONS: Thermal treatment significantly attenuated infiltration of inflammatory cells in adventitia and suppressed neointimal thickening in cuff-injured arteries with the enhancement of HSP72 expression and suppression of oxidative stress.

Ultrastructural examination of rabbit aortic wall following high-fat diet feeding and selenium supplementation: a transmission electron microscopy study.

Experiments were carried out to examine the changes occurring in the wall of rabbit aortae following high-fat diet (HFD) feeding as well as HFD + selenium supplementation. Male New Zealand White rabbits were divided into three groups-control, HFD-fed and HFD + Se supplementation-and were treated for three months. The study depicted that levels of serum total cholesterol and triglycerides were markedly increased in the HFD-fed group as compared with control animals. However, in the HFD + Se-fed group, these levels were markedly suppressed vis-à-vis animals fed on HFD only. Development of atherogenic and atheromatic plaques has been shown at the light microscopy level in HFD-fed rabbits, whereas these developments were not visible in the HFD + Se-fed rabbits. Transmission electron microscopy findings indicated altered ultrastructure in the endothelial cells of the intimal layer as well as smooth-muscle cells of the medial layer in HFD-fed animals. However, these findings indicated normal ultrastructure in most of the cells, with little ultrastructural alterations from animals supplemented with Se along with HFD feeding. The study on the whole depicted the ability of Se to inhibit the onset of progression of aortic disease and hence has relevance to its therapeutic potential.

Oral everolimus inhibits in-stent neointimal growth.

BACKGROUND: Rapamycin (sirolimus)-eluting stents are associated with reduced restenosis rates in animal studies and initial human trials. The present study evaluated whether orally administered everolimus (a macrolide of the same family as sirolimus) inhibits in-stent neointimal growth in rabbit iliac arteries. METHODS AND RESULTS: New Zealand white rabbits were randomized to everolimus 1.5 mg/kg per day starting 3 days before stenting and reduced to 1 mg/kg per day from days 14 to 28 (group 1), everolimus 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days (group 2), or matching placebo for each group. Drugs were administered by oral gavage. Stents were deployed in both iliac arteries, and arteries were harvested 28 days after stenting. Group 1 everolimus-treated rabbits experienced weight loss and anorexia, which resolved after the everolimus dose was lowered on day 14. Group 2 animals were healthy for the duration of everolimus dosing. Both everolimus treatment groups significantly reduced in-stent neointimal growth (46% reduction and 42% reduction in intimal thickness in groups 1 and 2, respectively). In group 2 everolimus-treated animals, the neointima was healed or healing, characterized by stent struts covered by a thin neointima, overlying endothelial cells, and only small foci of fibrin. Scanning electron microscopy showed >80% stent surface endothelialization in group 2 everolimus-treated rabbits. CONCLUSIONS: Oral everolimus suppresses in-stent neointimal growth in the rabbit iliac artery. At a dose of 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days, everolimus was well tolerated and was associated with significant neointimal healing.

Saratin, an inhibitor of von Willebrand factor-dependent platelet adhesion, decreases platelet aggregation and intimal hyperplasia in a rat carotid endarterectomy model.

PURPOSE: Post-carotid endarterectomy, thrombosis, and intimal hyperplasia may be decreased by the inhibition of platelet adhesion and activation. In this study, a novel agent, saratin, was used to inhibit platelet-to-collagen adhesion in a rat carotid endarterectomy model. Saratin is a recombinant protein isolated from the saliva of the medicinal leech Hirudo medicinalis, which is thought to act by binding to collagen, and inhibits von Willebrand factor-collagen interaction under conditions of increased shear and therefore, the adherence and activation of platelets at the vessel wall. Saratin has the advantage of being a nonsystemic, site-specific topical application. METHODS: A rat carotid endarterectomy model was used in which an open technique with arteriotomy and intimectomy was used. Saratin was applied to the endarterectomized surface of the carotid artery before arterial closure. End point measurements included platelet adhesion, thrombosis rate, intimal hyperplasia development, bleeding times, and platelet counts. Electron micrographs of carotid arteries were used for quantitative analysis of platelet aggregation and platelet counts. Intimal hyperplasia and thrombosis were assessed with computer-assisted morphometric analysis of elastin-stained carotid artery sections with direct measurement of the intimal hyperplasia area. RESULTS: The topical application of saratin significantly decreased platelet adhesion compared with controls at 3 hours after carotid endarterectomy (64 +/- 17 vs 155 +/- 33 platelets per grid, P = .05), and 24 hours after carotid endarterectomy (35 +/- 11 vs 149 +/- 37 platelets per grid, P = .0110), respectively. A percent luminal stenosis, as a measure of intimal hyperplasia, was significantly decreased with saratin application compared with controls (10.9% +/- 1.8% vs 29.8% +/- 6.8%, P = .0042). This decrease in intimal hyperplasia formation correlated with the inhibition of platelet adhesion. Thirty-three percent of control arteries were found to be thrombosed 2 weeks after carotid endarterectomy compared with a 0% thrombosis rate in the saratin-treated group (P = .0156). No increased bleeding was encountered along the arterial suture line in the saratin group. Bleeding times and systemic platelet counts were not found to change significantly in the saratin-treated rats compared with control rats at 3 and 24 hours after endarterectomy. CONCLUSION: Saratin significantly decreased platelet adhesion, intimal hyperplasia, luminal stenosis, and thrombosis after carotid endarterectomy in rats. Saratin did not increase suture line bleeding or bleeding times, and did not decrease platelet counts. Saratin may serve as a topical agent to be used for the site-specific inhibition of thrombosis and intimal hyperplasia after vascular manipulation.

Effect of short-term treatment with a monoclonal antibody to P-selectin on balloon catheter-induced: intimal hyperplasia, re-endothelialization, and attenuation of endothelial-dependent relaxation.

The effects of an anti-P-selectin monoclonal antibody (MAb, PB1.3; Cytel Corporation) on neoendothelialization; neoendothelial function, as evidenced by acetylcholine-induced relaxation (nitric oxide formation); and intimal hyperplasia following embolectomy catheter-induced injury to the rabbit thoracic aorta were investigated. Catheter injury was induced in two groups of New Zealand White rabbits. One group received no treatment, while the second group received short-term treatment with the MAb (i.p., immediately before and 12 h after induction of catheter injury). A third group underwent a sham operation and served as uninjured controls. Following sacrifice at 2 weeks after injury, aortic rings were assessed for degree of intimal hyperplasia, neoendothelial morphology (scanning electron microscopy), and acetylcholine-induced relaxation. Aortic tissue from catheter-injured animals that received treatment exhibited improved neoendothelial morphology, as compared with tissue from untreated but catheterized animals; however, no statistically significant attenuation of the hyperplastic response or improvement in the attenuated neoendothelial-dependent acetylcholine-induced relaxant response that is characteristic of neoendothelium that forms after catheter denudation was observed. These data suggest that short-term attenuation of P-selectin-mediated polymorphonuclear leukocyte (PMN)/endothelium, PMN/platelet interactions, and/or thrombin formation beneficially affects neoendothelialization of the vascular wall following balloon catheter-induced injury.