Adenovirus-mediated gene transfer of fibromodulin inhibits neointimal hyperplasia in an organ culture model of human saphenous vein graft disease

Ranjzad, Parisa; Salem, Husein K.; Kingston, Paul A.

doi:10.1038/gt.2009.63

Cited by 24 publications

(22 citation statements)

References 35 publications

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“…In a study by Ranjzad et al, 41 both the neointima and the neointimal collagen content was found to be decreased in human veins, after overexpression of fibromodulin through adenovirusmediated gene transfer ex vivo. The effects were found to be mediated, at least in part, by antagonism of transforming growth factor-β1 and collagen homeostasis.…”

Section: Discussionmentioning

confidence: 95%

Fibromodulin Deficiency Reduces Low-Density Lipoprotein Accumulation in Atherosclerotic Plaques in Apolipoprotein E–Null Mice

Shami

Gustafsson

Kalamajski

et al. 2013

ATVB

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Objective-The aim of this study was to analyze how an altered collagen structure affects development of atherosclerotic plaques. Methods and Results-Fibromodulin-null mice develop an abnormal collagen fibril structure. In apolipoprotein E (ApoE)-null and ApoE/fibromodulin-null mice, a shear stress-modifying carotid artery cast induced formation of atherosclerotic plaques of different phenotypes; inflammatory in low-shear stress regions and fibrous in oscillatory shear stress regions. Electron microscopy showed that collagen fibrils were thicker and more heterogeneous in oscillatory shear stress lesions from ApoE/fibromodulin-null mice. Low-shear stress lesions were smaller in ApoE/fibromodulin-null mice and contained less lipids. Total plaque burden in aortas stained en face with Oil Red O, as well as lipid accumulation in aortic root lesions, was also decreased in ApoE/fibromodulin-null mice. In addition, lipid accumulation in RAW264.7 macrophages cultured on fibromodulin-deficient extracellular matrix was decreased, whereas levels of interleukin-6 and -10 were increased. Our results show that an abnormal plaque collagen fibril structure can influence atherosclerotic plaque development. Conclusion-The present findings suggest a more complex role for collagen in plaque stability than previously anticipated, in that it may promote lipid-accumulation and inflammation at the same time as it provides mechanical stability.

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Section: Discussionmentioning

confidence: 95%

Fibromodulin Deficiency Reduces Low-Density Lipoprotein Accumulation in Atherosclerotic Plaques in Apolipoprotein E–Null Mice

Shami

Gustafsson

Kalamajski

et al. 2013

ATVB

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“…Human saphenous veins (SVs) were collected from patients after coronary artery bypass surgery and performed as described previously (Ranjzad et al, 2009). In brief, the SVs were opened longitudinally and cut transversely into 0.5-cm segments.…”

Section: Methodsmentioning

confidence: 99%

Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

Cai

Knight

Guo

et al. 2012

J Pharmacol Exp Ther

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Abnormal vascular smooth muscle cell (SMC) activation is associated with various vascular disorders such as atherosclerosis, in-stent restenosis, vein graft disease, and transplantationassociated vasculopathy. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. However, its role in pathological vascular remodeling remains unexplored. Herein, we show that systemic administration of vinpocetine significantly reduced neointimal formation in carotid arteries after ligation injury. Vinpocetine also markedly decreased spontaneous remodeling of human saphenous vein explants in ex vivo culture. In cultured SMCs, vinpocetine dose-dependently suppressed cell proliferation and caused G 1 -phase cell cycle arrest, which is associated with a decrease in cyclin D1 and an increase in p27Kip1 levels. In addition, vinpocetine dose-dependently inhibited platelet-derived growth factor (PDGF)-stimulated SMC migration as determined by the two-dimensional migration assays and three-dimensional aortic medial explant invasive assay. Moreover, vinpocetine significantly reduced PDGF-induced type I collagen and fibronectin expression. It is noteworthy that PDGF-stimulated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), but not protein kinase B, was specifically inhibited by vinpocetine. Vinpocetine powerfully attenuated intracellular reactive oxidative species (ROS) production, which largely mediates the inhibitory effects of vinpocetine on ERK1/2 activation and SMC growth. Taken together, our results reveal a novel function of vinpocetine in attenuating neointimal hyperplasia and pathological vascular remodeling, at least partially through suppressing ROS production and ERK1/2 activation in SMCs. Given the safety profile of vinpocetine, this study provides insight into the therapeutic potential of vinpocetine in proliferative vascular disorders.

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“…Using a series of adenoviruses and the human ex-vivo model, it was reported that fibromodullin was superior to decorin overexpression in reducing neointimal area and thickness in human saphenous vein segments at 14 days. 93 An alternate approach using Activin A to alter the contractile properties of VSMCs, led to a reduction in neointimal parameters in a rat model. 94 Therefore, there remains a number of strategies of potential benefit to the prevention of vein graft disease.…”

Section: Studies Using Gene Therapy For Vein Graftsmentioning

confidence: 99%

Vein graft failure: current clinical practice and potential for gene therapeutics

et al. 2012

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Autologous saphenous vein is commonly used as a conduit to bypass atherosclerotic lesions in coronary and femoral arteries. Despite the wide use of arterial conduits, which are less susceptible to complications and failure, as alternative conduits, the saphenous vein will continue to be used in coronary artery bypass grafting until acceptable alternative approaches are evaluated. Hence, preservation of vein graft patency is essential for the long-term success. Gene therapy is attractive in this setting as an ex-vivo technology to genetically manipulate the conduit before grafting. The use of safe and efficient vectors for delivery is a necessity as well as a strategy to improve patency in the long term. Here, we review the current clinical practice, the pathogenesis of bypass graft failure and adenovirus-mediated gene therapy strategies designed to improve late vein graft failure by modulation of smooth muscle cells in the vein wall.

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Adenovirus-mediated gene transfer of fibromodulin inhibits neointimal hyperplasia in an organ culture model of human saphenous vein graft disease

Cited by 24 publications

References 35 publications

Fibromodulin Deficiency Reduces Low-Density Lipoprotein Accumulation in Atherosclerotic Plaques in Apolipoprotein E–Null Mice

Fibromodulin Deficiency Reduces Low-Density Lipoprotein Accumulation in Atherosclerotic Plaques in Apolipoprotein E–Null Mice

Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

Vein graft failure: current clinical practice and potential for gene therapeutics

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