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Kimihiro Komori - One of the best experts on this subject based on the ideXlab platform.
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Dipeptidyl peptidase 4 inhibitor reduces Intimal Hyperplasia in rabbit autologous jugular vein graft under poor distal runoff.
Journal of Vascular Surgery, 2016Co-Authors: Akio Koyama, Kimihiro Komori, Ryo Otsuka, Junko Kajikuri, Takeo ItohAbstract:Background Dipeptidyl peptidase 4 inhibitors are widely used in patients with type 2 diabetes mellitus to accomplish glycemic control through an increase in the blood glucagon-like peptide 1 (GLP-1) concentration. These agents also inhibit vascular inflammation (eg, in atherosclerosis). This study was undertaken to determine whether and how vildagliptin (a potent dipeptidyl peptidase 4 inhibitor) might reduce Intimal Hyperplasia in vein grafts. Methods Twelve rabbits were randomly divided into two groups; one group received vildagliptin orally (10 mg/kg/d; n = 6), whereas the control group (n = 6) did not. Vildagliptin administration was started 7 days before rabbits underwent interposition reversed autologous jugular vein grafting and ended at graft harvesting (28 days after the operation). Histochemical changes in the vascular wall were examined, as were changes in the acetylcholine-induced effects on the endothelial Ca 2+ concentration ([Ca 2+ ] i ) and endothelium-dependent relaxation. Results Under fasting conditions, vildagliptin increased the plasma GLP-1 concentration, without affecting plasma glucose or insulin. Acetylcholine induced endothelium-dependent relaxation only in the vildagliptin group, and this was blocked by the nitric oxide synthase inhibitor N ω -nitro-l-arginine. Acetylcholine did not modify the endothelial [Ca 2+ ] i in either the control or vildagliptin group. Intimal Hyperplasia was significantly less in the vildagliptin group (0.11 ± 0.02 mm, n = 5) than in the controls (0.31 ± 0.06 mm, n = 4; P Conclusions Vildagliptin increased the plasma GLP-1 concentration. It also enhanced acetylcholine-induced [Ca 2+ ] i -independent endothelial nitric oxide release and reduced vein graft Intimal Hyperplasia, independently of any glycemic control action.
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role of girdin in Intimal Hyperplasia in vein grafts and efficacy of atelocollagen mediated application of small interfering rna for vein graft failure
Journal of Vascular Surgery, 2014Co-Authors: Hiroki Miyachi, Kimihiro Komori, Atsushi Enomoto, Yoshiki Murakumo, Takuya Kato, Naoya Asai, Masahide TakahashiAbstract:Objective Intimal Hyperplasia is a major obstacle to patency in grafted veins. Although migration and proliferation of vascular smooth muscle cells (SMCs) pivotally affect the vascular remodeling process, no therapy has been established to prevent Intimal Hyperplasia of vein grafts. We previously reported that the actin-binding protein Girdin crucially affects arterial remodeling. In this study, we investigated the role of Girdin in venous SMCs and evaluated a therapeutic strategy for vein graft failure in vivo using small interfering RNA (siRNA) that targets Girdin . Methods We investigated the relationship between Girdin expression and Intimal Hyperplasia using a rabbit vein graft model. Vein grafts under low-flow conditions were performed in Japanese White rabbits. For in vitro analyses, we isolated primary venous SMCs from vein graft neointima. siRNA that targets Girdin was mixed with atelocollagen, which stabilizes and releases nucleic acid reagents slowly and is applied perivascularly to the vein grafts at operation. Intimal Hyperplasia was evaluated 4 weeks later. Results In the rabbit model, increased Girdin expression was seen in the neointima after the grafting operation. Using primary venous SMCs, we showed that Girdin is required for rearrangement of the actin cytoskeleton in venous SMCs and that siRNA-mediated Girdin knockdown significantly reduced venous SMC migration and proliferation. Girdin knockdown via perivascular application of siRNA using atelocollagen markedly reduced Intimal thickening after the grafting operation. Conclusions Depletion of Girdin attenuated venous SMCs migration and proliferation in vitro and Intimal Hyperplasia in vein grafts in vivo. Our findings suggest that Girdin affects migration and proliferation of vascular SMCs in vein grafts and that controlled release of Girdin siRNA using atelocollagen could be a novel therapeutic strategy for vein graft failure.
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controlled release of small interfering rna targeting midkine attenuates Intimal Hyperplasia in vein grafts
Journal of Vascular Surgery, 2006Co-Authors: Hiroshi Banno, Kimihiro Komori, Yoshifumi Takei, Takashi Muramatsu, Kenji KadomatsuAbstract:Objective Intimal Hyperplasia is a major obstacle to patency after vein grafting. Despite of a diverse array of trials to prevent it, a satisfactory therapeutic strategy for clinical use has not been established. However, sufficient inhibition of early stages of Intimal Hyperplasia may prevent this long-term progressive disease. Midkine (MK) is a heparin-binding growth factor that was originally discovered as the product of a retinoic acid-responsive gene. We previously demonstrated that MK-deficient mice exhibit a striking reduction of neointima formation in a restenosis model, which is reversed on systemic MK administration. In this study, we evaluated a strategy of using small interfering RNA (siRNA) targeting MK as a therapy for vein graft failure. Methods We first made a highly effective siRNA to rabbit MK. Jugular vein-to-carotid artery interposition vein grafts, which are applied to a low flow condition, were made in Japanese white rabbits. Small interfering RNA mixed with atelocollagen was administrated to the external wall of grafted veins. Cy3-conjugated stabilized siRNA was used to confirm its stability and successful transfer into the vein graft wall. NeoIntimal Hyperplasia was evaluated 4 weeks after the operation. The proliferation index and leukocyte infiltration were determined. Results MK expression was induced and reached the maximum level 7 days after operation. Fluorescence of Cy3-labeled siRNA could be detected in the graft wall even 7 days after operation. Knockdown of the gradually increasing expression was achieved by perivascular application of siRNA using atelocollagen. The intima-media ratio and the intima thickness at 28 days after grafting were both reduced >90% by this treatment compared with controls. This phenomenon was preceded by significant reductions of inflammatory cell recruitment to the vessel walls and subsequent cell proliferation in MK siRNA-treated grafts. Conclusions These results suggest that midkine is a candidate molecular target for preventing vein graft failure. Furthermore, for clinical applications of siRNA, a single intraoperative atelocollagen-based nonviral delivery method could be a reliable approach to achieve maximal function of siRNA in vivo. This strategy may be a useful and practical form of gene therapy against human vein graft failure.
Per-otto Hagen - One of the best experts on this subject based on the ideXlab platform.
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pathobiology of Intimal Hyperplasia
British Journal of Surgery, 2005Co-Authors: Mark G. Davies, Per-otto HagenAbstract:In the current vascular interventional environment, high restenosis rates have increased awareness of the significance of Intimal Hyperplasia, a chronic structural lesion that develops after vessel wall injury, and which can lead to luminal stenosis and occlusion. Intimal Hyperplasia may be defined as the abnormal migration and proliferation of vascular smooth muscle cells with associated deposition of extracellular connective tissue matrix. The pathology of Intimal Hyperplasia is reviewed with particular attention to its physiology, pharmacology, cell biology and molecular biology.
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lazaroid therapy methylaminochroman u83836e reduces vein graft Intimal Hyperplasia
Journal of Surgical Research, 1996Co-Authors: Mark G. Davies, Lizzie Barber, Helge Dalen, Einar Svendsen, Per-otto HagenAbstract:The development of Intimal Hyperplasia is now recognized as a major impediment to graft patency and recent studies suggest that the infiltration of polymorphonucleocytes and oxygen free radical mediated injury are involved in the early development of Intimal Hyperplasia. This study examines the effect of a methylaminochroman, U83836E (Upjohn Company), a second generation lazaroid, in controlling the development of Intimal Hyperplasia and its associated smooth muscle cell physiological responses in an experimental model of vein bypass grafting. Twenty New Zealand White rabbits had a right carotid interposition bypass graft using the ipsilateral external jugular vein. Ten animals received chronic oral therapy with U83836E (10 mg/kg/day; begun 5 days before surgery and continued until harvest) and 10 control animals received vehicle only. All animals were sacrificed on the 28th postoperative day. Vein grafts were harvested either for morphology/videomorphometry (n = 6 per group) or for in vitro isometric tension studies (n = 4; four 5-mm rings per graft). The incorporation of [3H]thymidine into the cellular DNA of serum-stimulated rabbit aortic smooth muscle cells (passage 6th to 9th) was also assessed in the presence of increasing concentrations of U83836E (10(-9) to 10(-4) M). Treatment with U83836E produced a 41% decrease in overall mean Intimal thickness in the U83836E-treated vein grafts compared to untreated vein grafts (P = 0.003). There were no differences in the medial thicknesses or luminal dimensions of the control and treated vein grafts. U83836E induced norepinephrine hypersensitivity in both jugular veins and vein grafts compared to controls. Other physiological contractile responses of the jugular veins and vein grafts were unaltered by U83836E. U83836E did not inhibit the in vitro [3H] thymidine incorporation in a dose-dependent manner until very high concentration when there was a significant and precipitous response with an IC(50) of 67 microM (114 microgram/ml) and a maximal inhibition of 97 +/- 2% (mean +/- SEM) at 80 microM (137 microgram/ml). Therapy with the methylaminochroman, U83836E, is beneficial in controlling the early development of Intimal Hyperplasia without significant changes in the physiological responses of the smooth muscle cells.
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control of the structural and functional consequences of vein graft Intimal Hyperplasia with a 21 aminosteroid u74389g
European Journal of Vascular Surgery, 1994Co-Authors: Mark G. Davies, Lizzie Barber, Helge Dalen, Einar Svendsen, Per-otto HagenAbstract:Following angioplasty and vein bypass grafting, there is endothelial cell injury, infiltration of leukocytes and smooth muscle cell (SMC) proliferation leading to Intimal Hyperplasia which may result in stenosis and can lead to eventual occlusion. This study examines the effect of the 21-aminosteroid U74389G (Upjohn Company), on the formation of vein graft Intimal Hyperplasia in vivo and on SMC DNA synthesis and proliferation in vitro . Twenty New Zealand White rabbits had a right carotid interposition bypass graft using the ipsilateral external jugular vein. Ten animals received chronic oral therapy with U74389G (25 mg/kg/day; begun 5 days before surgery and continued until harvest) and 10 control animals received vehicle only. All animals were sacrificed on the 28th postoperative day. Vein grafts were harvested either for histology/videomorphometry ( n = 6 per group) or for in vitro isometric tension studies ( n = 4; four 5mm rings per graft). The incorporation of [ 3 H]thymidine into the cellular DNA of serum-stimulated rabbit aortic SMC (passage 6th to 12th) was assessed in the presence of increasing concentrations of U74389G (10 −9 to 10 −4 M). The effect of U74389G on in vitro cell proliferation was also assessed. Treatment with U74389G produced a 44% decrease in overall mean Intimal thickness from 82 ± 1 μM (mean ± s.e.m. ) in the controls to 57 ± 10 μM in the U74389G treated vein grafts ( p = 0.003). Furthermore, there was a 40% increase in overall luminal areas of the treated vein grafts compared to controls (19.4 ± 2.9 vs . 13.9 ± 2.0 mm 2 ; p = 0.13; mean ± s.e.m. ) while there was no statistical differences in the medial thicknesses of the control and treated vein grafts. The vasomotor function of the vein grafts was not altered by U74389G. Incubation with U74389G inhibited in vitro [ 3 H]thymidine incorporation of serum-stimulated rabbit SMC with an IC 50 of 6.9 μM (4.9 μg/ml) and a maximal inhibition of 67 ± 3% (mean ± s.e.m. ) at 10μM. In addition, the presence of U74389G produced a concentration dependent inhibition of in vitro cell proliferation. This study shows that a 21-aminosteroid, U74389G, significantly reduced Intimal Hyperplasia in experimental vein grafts, but did not modulate the increased vasoconstrictive properties of the grafts. In addition, U74389G inhibited SMC DNA synthesis in vitro . The in vivo reduction in Intimal Hyperplasia together with an increased luminal area would mitigate against the development of vein graft stenosis. However, the absence of vasomotor changes suggests that the tendency towards vasospasm remains in the treated grafts. Furthermore, the inhibition of SMC proliferation by U74389G suggests that it may have properties unrelated to its antioxidant activity and thus, may have additional benefits in controlling the development of Intimal Hyperplasia.
Thomas Franz - One of the best experts on this subject based on the ideXlab platform.
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constrictive external nitinol meshes inhibit vein graft Intimal Hyperplasia in nonhuman primates
The Journal of Thoracic and Cardiovascular Surgery, 2008Co-Authors: Peter Zilla, Paul Human, Michael F Wolf, Wilhelm Lichtenberg, Nasser Rafiee, Deon Bezuidenhout, Nazlia Samodien, Christian Schmidt, Thomas FranzAbstract:Objective External mesh support of vein grafts has been shown to mitigate the formation of Intimal Hyperplasia. The aim of the present study was to address the issue of optimal mesh size in a nonhuman primate model that mimics the dimensional mismatch typically encountered between clinical vein grafts and their target arteries. Methods The effect of mesh size on Intimal Hyperplasia and endothelial preservation was assessed in bilateral femoral interposition grafts in Chacma baboons (n Σ = 32/n = 8 per mesh size). No mesh support (group I) was compared with external nitinol meshes at three different sizes: loose fitting (group II), 25% diameter constricting (group III), and 50% diameter constricting (group IV). Mesh sizes were seen not only in isolation but also against the background of anastomotic size mismatch at implantation, expressed as quotient of cross-sectional area of host artery to vein graft (Q C ). Results Significant amounts of Intimal Hyperplasia were found in group I (Q C median 0.20; Intimal Hyperplasia 6 weeks=1.63 ± 0.34 mm 2 ; Intimal Hyperplasia 12 weeks=1.73 ± 0.5 mm 2 ) and group II (Q C median 0.25; Intimal Hyperplasia 6 weeks=1.96 ± 1.64 mm 2 ; Intimal Hyperplasia 12 weeks=2.88 ± 1.69 mm 2 ). In contrast, group III (Q C median 0.45; Intimal Hyperplasia 6 weeks=0.08 ± 0.13 mm 2 ; Intimal Hyperplasia 12 weeks=0.18 ± 0.32 mm 2 ) and IV (Q C median 1.16; Intimal Hyperplasia 6 weeks=0.02 ± 0.03 mm 2 ; Intimal Hyperplasia 12 weeks=0.11 ± 0.10 mm 2 ) showed dramatically suppressed Intimal Hyperplasia ( P P Conclusion By using an animal model that addressed the clinical phenomenon of diameter discrepancy between vein graft and bypassed artery, we could demonstrate that suppression of Intimal Hyperplasia required constrictive mesh sizes.
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constrictive external nitinol meshes inhibit vein graft Intimal Hyperplasia in nonhuman primates
The Journal of Thoracic and Cardiovascular Surgery, 2008Co-Authors: Peter Zilla, Paul Human, Michael F Wolf, Wilhelm Lichtenberg, Nasser Rafiee, Deon Bezuidenhout, Nazlia Samodien, Christian Schmidt, Thomas FranzAbstract:OBJECTIVE: External mesh support of vein grafts has been shown to mitigate the formation of Intimal Hyperplasia. The aim of the present study was to address the issue of optimal mesh size in a nonhuman primate model that mimics the dimensional mismatch typically encountered between clinical vein grafts and their target arteries. METHODS: The effect of mesh size on Intimal Hyperplasia and endothelial preservation was assessed in bilateral femoral interposition grafts in Chacma baboons (n(Sigma) = 32/n = 8 per mesh size). No mesh support (group I) was compared with external nitinol meshes at three different sizes: loose fitting (group II), 25% diameter constricting (group III), and 50% diameter constricting (group IV). Mesh sizes were seen not only in isolation but also against the background of anastomotic size mismatch at implantation, expressed as quotient of cross-sectional area of host artery to vein graft (Q(C)). RESULTS: Significant amounts of Intimal Hyperplasia were found in group I (Q(C) median 0.20; Intimal Hyperplasia 6 weeks = 1.63 +/- 0.34 mm(2); Intimal Hyperplasia 12 weeks = 1.73 +/- 0.5 mm(2)) and group II (Q(C) median 0.25; Intimal Hyperplasia 6 weeks = 1.96 +/- 1.64 mm(2); Intimal Hyperplasia 12 weeks = 2.88 +/- 1.69 mm(2)). In contrast, group III (Q(C) median 0.45; Intimal Hyperplasia 6 weeks = 0.08 +/- 0.13 mm(2); Intimal Hyperplasia 12 weeks = 0.18 +/- 0.32 mm(2)) and IV (Q(C) median 1.16; Intimal Hyperplasia 6 weeks = 0.02 +/- 0.03 mm(2); Intimal Hyperplasia 12 weeks = 0.11 +/- 0.10 mm(2)) showed dramatically suppressed Intimal Hyperplasia (P < .01) at both time points. Endothelial integrity was only preserved in group IV (P < .05). There were no significant differences in vascularization and inflammation in either interlayer or intergroup comparisons. CONCLUSION: By using an animal model that addressed the clinical phenomenon of diameter discrepancy between vein graft and bypassed artery, we could demonstrate that suppression of Intimal Hyperplasia required constrictive mesh sizes.
Alban Longchamp - One of the best experts on this subject based on the ideXlab platform.
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nitric oxide deficit drives Intimal Hyperplasia in mouse models of hypertension
European Journal of Vascular and Endovascular Surgery, 2016Co-Authors: Florent Allagnat, Alban Longchamp, Jacquesantoine Haefliger, Martine Lambelet, Xavier Berard, Lucia Mazzolai, Jeanmarc Corpataux, Sebastien DegliseAbstract:Objective To evaluate the impact of different types of hypertension on the development of Intimal Hyperplasia (IH). Method Genetic, surgical, and pharmacological models of hypertension were used to compare IH formation in a murine model of carotid artery ligation (CAL). CAL was performed in normotensive WT male mice and in three mouse models of hypertension: (1) L-NAME (Nω-nitro-l-arginine-methyl-ester) treatment for 2 weeks prior to CAL to instate renin-independent hypertension; (2) 2K1C (two kidneys, one clip) surgery 1 week prior to CAL to induce renin-dependent hypertension; (3) Cx40−/− mice, a genetic model of renin-dependent hypertension. Mice were sacrificed prior to CAL or 3, 14, or 28 days post CAL. Data collection included tail blood pressure measurements, and morphometric and histological assessment of the ligated carotids. Results CAL triggered the formation of a VSMC-rich neointima layer after 14–28 days, which was increased in all hypertensive mice. Despite similarly increased blood pressure, L-NAME treated mice displayed more IH than all other hypertensive groups. In addition, L-NAME induced hypertension triggered more cell proliferation and recruitment of CD45 positive inflammatory cells to the ligated vessel wall compared with Cx40−/− or normotensive WT mice. Conclusions NO deficiency is a major aspect of vascular inflammation, VSMC proliferation, and IH in hypertensive conditions.
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connexin43 inhibition prevents human vein grafts Intimal Hyperplasia
PLOS ONE, 2015Co-Authors: Alban Longchamp, Florent Allagnat, Florian Alonso, Christopher Kuppler, Celine Dubuis, Charleskeith Ozaki, James R Mitchell, Scott A BerceliAbstract:Venous bypass grafts often fail following arterial implantation due to excessive smooth muscle cells (VSMC) proliferation and consequent Intimal Hyperplasia (IH). Intercellular communication mediated by Connexins (Cx) regulates differentiation, growth and proliferation in various cell types. Microarray analysis of vein grafts in a model of bilateral rabbit jugular vein graft revealed Cx43 as an early upregulated gene. Additional experiments conducted using an ex-vivo human saphenous veins perfusion system (EVPS) confirmed that Cx43 was rapidly increased in human veins subjected ex-vivo to arterial hemodynamics. Cx43 knock-down by RNA interference, or adenoviral-mediated overexpression, respectively inhibited or stimulated the proliferation of primary human VSMC in vitro. Furthermore, Cx blockade with carbenoxolone or the specific Cx43 inhibitory peptide 43gap26 prevented the burst in myoIntimal proliferation and IH formation in human saphenous veins. Our data demonstrated that Cx43 controls proliferation and the formation of IH after arterial engraftment.
Mark G. Davies - One of the best experts on this subject based on the ideXlab platform.
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pathobiology of Intimal Hyperplasia
British Journal of Surgery, 2005Co-Authors: Mark G. Davies, Per-otto HagenAbstract:In the current vascular interventional environment, high restenosis rates have increased awareness of the significance of Intimal Hyperplasia, a chronic structural lesion that develops after vessel wall injury, and which can lead to luminal stenosis and occlusion. Intimal Hyperplasia may be defined as the abnormal migration and proliferation of vascular smooth muscle cells with associated deposition of extracellular connective tissue matrix. The pathology of Intimal Hyperplasia is reviewed with particular attention to its physiology, pharmacology, cell biology and molecular biology.
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lazaroid therapy methylaminochroman u83836e reduces vein graft Intimal Hyperplasia
Journal of Surgical Research, 1996Co-Authors: Mark G. Davies, Lizzie Barber, Helge Dalen, Einar Svendsen, Per-otto HagenAbstract:The development of Intimal Hyperplasia is now recognized as a major impediment to graft patency and recent studies suggest that the infiltration of polymorphonucleocytes and oxygen free radical mediated injury are involved in the early development of Intimal Hyperplasia. This study examines the effect of a methylaminochroman, U83836E (Upjohn Company), a second generation lazaroid, in controlling the development of Intimal Hyperplasia and its associated smooth muscle cell physiological responses in an experimental model of vein bypass grafting. Twenty New Zealand White rabbits had a right carotid interposition bypass graft using the ipsilateral external jugular vein. Ten animals received chronic oral therapy with U83836E (10 mg/kg/day; begun 5 days before surgery and continued until harvest) and 10 control animals received vehicle only. All animals were sacrificed on the 28th postoperative day. Vein grafts were harvested either for morphology/videomorphometry (n = 6 per group) or for in vitro isometric tension studies (n = 4; four 5-mm rings per graft). The incorporation of [3H]thymidine into the cellular DNA of serum-stimulated rabbit aortic smooth muscle cells (passage 6th to 9th) was also assessed in the presence of increasing concentrations of U83836E (10(-9) to 10(-4) M). Treatment with U83836E produced a 41% decrease in overall mean Intimal thickness in the U83836E-treated vein grafts compared to untreated vein grafts (P = 0.003). There were no differences in the medial thicknesses or luminal dimensions of the control and treated vein grafts. U83836E induced norepinephrine hypersensitivity in both jugular veins and vein grafts compared to controls. Other physiological contractile responses of the jugular veins and vein grafts were unaltered by U83836E. U83836E did not inhibit the in vitro [3H] thymidine incorporation in a dose-dependent manner until very high concentration when there was a significant and precipitous response with an IC(50) of 67 microM (114 microgram/ml) and a maximal inhibition of 97 +/- 2% (mean +/- SEM) at 80 microM (137 microgram/ml). Therapy with the methylaminochroman, U83836E, is beneficial in controlling the early development of Intimal Hyperplasia without significant changes in the physiological responses of the smooth muscle cells.
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control of the structural and functional consequences of vein graft Intimal Hyperplasia with a 21 aminosteroid u74389g
European Journal of Vascular Surgery, 1994Co-Authors: Mark G. Davies, Lizzie Barber, Helge Dalen, Einar Svendsen, Per-otto HagenAbstract:Following angioplasty and vein bypass grafting, there is endothelial cell injury, infiltration of leukocytes and smooth muscle cell (SMC) proliferation leading to Intimal Hyperplasia which may result in stenosis and can lead to eventual occlusion. This study examines the effect of the 21-aminosteroid U74389G (Upjohn Company), on the formation of vein graft Intimal Hyperplasia in vivo and on SMC DNA synthesis and proliferation in vitro . Twenty New Zealand White rabbits had a right carotid interposition bypass graft using the ipsilateral external jugular vein. Ten animals received chronic oral therapy with U74389G (25 mg/kg/day; begun 5 days before surgery and continued until harvest) and 10 control animals received vehicle only. All animals were sacrificed on the 28th postoperative day. Vein grafts were harvested either for histology/videomorphometry ( n = 6 per group) or for in vitro isometric tension studies ( n = 4; four 5mm rings per graft). The incorporation of [ 3 H]thymidine into the cellular DNA of serum-stimulated rabbit aortic SMC (passage 6th to 12th) was assessed in the presence of increasing concentrations of U74389G (10 −9 to 10 −4 M). The effect of U74389G on in vitro cell proliferation was also assessed. Treatment with U74389G produced a 44% decrease in overall mean Intimal thickness from 82 ± 1 μM (mean ± s.e.m. ) in the controls to 57 ± 10 μM in the U74389G treated vein grafts ( p = 0.003). Furthermore, there was a 40% increase in overall luminal areas of the treated vein grafts compared to controls (19.4 ± 2.9 vs . 13.9 ± 2.0 mm 2 ; p = 0.13; mean ± s.e.m. ) while there was no statistical differences in the medial thicknesses of the control and treated vein grafts. The vasomotor function of the vein grafts was not altered by U74389G. Incubation with U74389G inhibited in vitro [ 3 H]thymidine incorporation of serum-stimulated rabbit SMC with an IC 50 of 6.9 μM (4.9 μg/ml) and a maximal inhibition of 67 ± 3% (mean ± s.e.m. ) at 10μM. In addition, the presence of U74389G produced a concentration dependent inhibition of in vitro cell proliferation. This study shows that a 21-aminosteroid, U74389G, significantly reduced Intimal Hyperplasia in experimental vein grafts, but did not modulate the increased vasoconstrictive properties of the grafts. In addition, U74389G inhibited SMC DNA synthesis in vitro . The in vivo reduction in Intimal Hyperplasia together with an increased luminal area would mitigate against the development of vein graft stenosis. However, the absence of vasomotor changes suggests that the tendency towards vasospasm remains in the treated grafts. Furthermore, the inhibition of SMC proliferation by U74389G suggests that it may have properties unrelated to its antioxidant activity and thus, may have additional benefits in controlling the development of Intimal Hyperplasia.
