Preventing intimal thickening of vein grafts in vein artery bypass using STAT-3 siRNA (original) (raw)
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Journal of Vascular Surgery, 2009
Vascular smooth muscle cell (SMC) migration and proliferation contribute to the pathobiology of atherosclerosis and of instent restenosis, transplant vasculopathy and vein by-pass graft failure. Since mevalonate (MVA) and other intermediates of cholesterol biosynthesis (isoprenoids) are necessary for cell migration and proliferation, inhibition of 3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase, the rate limiting step of the MVA pathway, has the potential to result in antiatherosclerotic effect. Indeed statins, competitive inhibitors of the HMG-CoA reductase, have shown the capability to interfere with migration and proliferation of SMC in diverse experimental models. Here we summarize in vitro, in vivo, and ex-vivo evidence of the inhibitory effects of statins on SMC proliferation and migration and discuss the molecular mechanisms involved in their pharmacodynamic action. Altogether this evidence suggests direct vascular antiatherosclerotic properties of statins. However, it is important to mention that statins failed to prevent intimal-thickening when studied in clinical setting characterized by accelerated vascular SMC proliferation and migration (e.g., restenosis after PTCA and in-stent), thus leaving open the question on the clinical relevance of these direct vascular effects of statins.
Vascular-wall remodeling of 3 human bypass vessels: Organ culture and smooth muscle cell properties
The Journal of Thoracic and Cardiovascular Surgery, 2006
Objectives: Late graft occlusions after coronary artery bypass grafting have been ascribed to neointimal hyperplasia. Given the pivotal role of smooth muscle cells in the pathogenesis of neointimal hyperplasia and the phenotypic heterogeneity of smooth muscle cells across vessels, we hypothesized that differences in long-term graft patency are at least partly related to differences in smooth muscle cell properties. The aim of the present study was to compare the vascular-wall remodeling of human internal thoracic artery, radial artery, and saphenous vein bypass conduits. Methods: We evaluated the intimal thickening of the human graft segments in organ cultures (histopathology, morphometric, and immunofluorescence analyses) and assessed the properties of cultured smooth muscle cells isolated from these vessels in terms of cell proliferation (tritiated thymidine incorporation), migration (modified Boyden chamber), and collagen synthesis (tritiated proline incorporation). Results: The total vessel-wall growth index and the intimal growth index were significantly higher for saphenous vein rings than for radial artery and internal thoracic artery rings. Immunofluorescence analyses showed predominant involvement of smooth muscle cells in neointimal growth induced by organ culture of saphenous vein rings. Cell proliferation was significantly higher in saphenous vein smooth muscle cells than in radial artery smooth muscle cells and significantly higher in radial artery smooth muscle cells than in internal thoracic artery smooth muscle cells. Migration of smooth muscle cells from saphenous vein grafts was significantly greater than from internal thoracic artery or radial artery grafts. Collagen synthesis was similar in smooth muscle cells from internal thoracic artery, radial artery, and saphenous vein grafts. Conclusions: Ex vivo vascular-wall remodeling and smooth muscle cell intrinsic growth and migratory properties are dissimilar between arterial and venous grafts and might shed light on reported angiographic patency rates of these grafts.
Circulation, 1998
Background —Internal mammary artery (IMA) bypass grafts have a higher patency than saphenous vein (SV) grafts. Intimal hyperplasia of SV grafts is due to smooth muscle cell (SMC) proliferation and migration. We hypothesized that different SMC growth activity exists in IMA and SV, which may explain the different patencies of arterial and venous grafts. Methods and Results —SMCs were isolated from IMA and SV by explant culture and stimulated with serum or platelet-derived growth factor-BB (PDGF-BB). Cell growth was analyzed by explant outgrowth rate, 3 H-thymidine incorporation, or cell counting. PDGF receptor expression and autophosphorylation, regulation of mitogen-activated protein kinases (MAPKs), and cyclin-dependent kinase inhibitors (p27 Kip1 and p21 Cip1 ) were analyzed by molecular techniques. SMC outgrowth from explants by serum (20%) over a 20-day period was more pronounced in SV (37±5%) than in IMA (4±3%; P <.001) of the same patients. Serum (10%) increased cell number ...
Vascular Disease Prevention, 2008
Saphenous vein (SV) is an excellent conduit for revascularization, especially for patients with multi-vessel coronary artery disease and peripheral arterial disease. However, its patency is limited in comparison with arterial grafts. Vein graft occlusion is the result of intimal hyperplasia and accelerated development of atherosclerosis, a cellular response triggered by surgical trauma, hypoxia, and increased wall stress. Nevertheless, the cellular mechanisms of vascular disease following bypass graft implantation, especially the impact of vein preparation and surgical techniques are less known than those that occur after angioplasty. The present article reviews the molecular mechanisms of vein graft remodeling, specifically thrombosis, alteration in endothelial function, modification of signaling pathways leading to cell proliferation and migration, role of intracellular calcium and activation of matrix metalloproteinases. The procedures of vein harvesting are discussed from the point of view of its possible impact on graft remodeling. Special attention is devoted to the consequences of pressure distention of the vein during the preparation for grafting; and an alternative preparation, which allows overcoming vasospasm without distention is discussed. The effects of pharmacological treatment during the preparation procedure and during arterialization are also discussed. An external support of the graft has been suggested to reduce graft remodeling, and its effects on the vascular mechanisms during arterialization are also considered. In conclusion, adjustment of the vein harvesting and preparation procedures combined with pharmacological treatment targeting the vasoconstrictor and proliferative mechanisms could improve long term vein graft patency.
Statin therapy prevents expansive remodeling in venous bypass grafts
Atherosclerosis, 2012
Background: Venous grafts (VG) have high failure rates by 10 years in aortocoronary bypass surgery. We have previously shown that expansive remodeling followed by increased LDL retention are early atherosclerotic changes in experimental VG placed in the arterial circulation. The objective of this study was to determine whether statin therapy prevents these expansive remodeling changes. Methods and results: Reversed jugular vein-to-common carotid artery interposition graft was constructed in 27 cholesterol-fed (0.5%) rabbits. Rabbits were randomized either to control or atorvastatin (5 mg/kg/ day) groups, starting two weeks prior to vein graft implantation and continuing until sacrifice at 1 or 12 weeks post-surgery. Ultrasound measurements of arterial luminal cross-sectional area (CSA) were done at day 3 and at 4, 8 and 12 weeks post-surgery. Histomorphometric measurements were performed following sacrifice at 12 weeks. Atorvastatin treatment significantly decreased total plasma cholesterol levels at 4, 8 and 12 weeks (12 weeks: 6.7 AE 4.2 mmol/L versus control 38.7 AE 10.6 mmol/L, p < 0.0002). Atorvastatin significantly reduced expansive remodeling at 4, 8 and 12 weeks (lumen CSA: 44.6 AE 6.6 mm 2 versus control 77.6 AE 10.7 mm 2 , p < 0.0001). Intimal CSA by histomorphometry was also significantly reduced by atorvastatin at 12 weeks (5.59 AE 2.19 mm 2 versus control 9.57 AE 2.43 mm 2 , p < 0.01). VG macrophage infiltration, MMP-2 activity and metalloelastase activity were reduced in the atorvastatin treated group. Conclusion: Atorvastatin inhibits both expansive remodeling and intimal hyperplasia in arterialized VG, likely through inhibition of macrophage infiltration and reduction of tissue proteolytic activity. The mechanism proposed above may be important for preventing VG atherosclerosis and late VG failure.
Intimal growth and neovascularization in human stenotic vein grafts1
Journal of the American College of Surgeons, 2000
Background: Myointimal thickening and microvessel ingrowth are commonly observed in vein graft stenosis, which complicates a third of infrainguinal bypass procedures. But a direct correlation between these two features has not been established. Our purpose was to analyze the relationship between neovascularity and intimal thickness in human vein grafts. Study Design: Twenty-two explant stenotic vein grafts (STVG), 8 nonstenotic arterialized vein grafts (AVG), and 20 age-matched control greater saphenous veins (CGSV) were analyzed histologically and compared morphologically by light microscopy. Digitized computer image analysis was used to measure intimal thickness and quantitate microvessel ingrowth. Immunolocalization of endothelial cells around the lumen and in microvessels was determined using antibodies to factor VIII and to endothelial nitric oxide synthase (eNOS), respectively. Results: Focal areas of endothelial disruption and thrombus deposition were present in 23% (5 of 22) of stenotic vein grafts. The neointima of STVG grafts was two-and fourfold thicker than that of AVG and CGSV, respectively (p<0.0001). Microvessels were most frequently observed in the adventitia and media of STVG and increased in number with increasing intimal thickness (p<0.001 by ANOVA). Conclusions: A fourfold increased neointimal thickness in critically stenotic vein grafts is associated with increased medial and adventitial neovascularization. Remodeling alone with doubling of the intimal thickness in nonstenotic arterialized vein grafts does not appear to be associated with enhancement of the graft microvasculature. More specific observations using an experimental model may allow us to further define the role of angiogenesis in vein graft stenosis and to determine the therapeutic implications of such observations.
Topography of cell replication in human vein graft stenoses
Circulation, 1998
Analysis of the cellular composition of human autogenous vein graft lesions at the time of revision provides an opportunity to identify the cellular processes leading to the development of stenosis in humans after vascular reconstruction. Human vein graft-threatening stenotic lesions were identified by duplex scanning within 3 to 18 months after infrainguinal bypass and surgically removed. They were serially studied by immunocytochemistry for expression of the proliferating cell nuclear antigen (PCNA) in different cell types: alpha-actin-positive smooth muscle cells (SMCs), endothelial cells (ECs), monocytes, and macrophages. Proliferation indexes were separately obtained for each layer of the vessel wall by determining the mean percentage of PCNA-positive nuclei among the total number of nuclei present within the intima, the media, and the adventitia, respectively. The percentage distribution of the replicating cell types was also determined. We report that in autogenous vein graft...
Current siRNA targets in the prevention and treatment of intimal hyperplasia
Discovery medicine, 2014
Intimal hyperplasia (IH) is the leading cause of late vein and prosthetic bypass graft failure. Injury at the time of graft implantation leading to the activation of endothelial cells and dedifferentiation of vascular smooth muscle cells to a synthetic phenotype are known causes of IH. Prior attempts to develop therapy to mitigate these cellular changes to prevent IH and graft failure have failed. Small interfering RNA (siRNA) mediated targeted gene silencing is a promising tool to prevent IH. Several studies have been performed in this direction to target genes that are involved in IH. In this review we discuss siRNA targets that are being investigated for prevention and treatment of IH.