Inhibition of Neointimal Smooth Muscle Accumulation After Angioplasty by an Antibody to PDGF

Ferns, Gordon A.; Raines, Elaine W.; Sprugel, K. H.; Motani, Alykhan; Reidy, Michael A.; Ross, Russell

doi:10.1126/science.1653454

Cited by 1,021 publications

(491 citation statements)

References 32 publications

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“…36 The effect of TIMP-2 to inhibit neointima formation seen here was mediated by these criteria through selective inhibition of SMC migration. This conclusion is consistent with work on isolated rat SMC 19 and other work with synthetic MMP inhibitors.…”

Section: Figure 5 Effect Of Radtimp-2 Infection On Neointima Formatiomentioning

confidence: 74%

Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

et al. 1998

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Metalloproteinases (MMPs) are implicated in neointima for-21.8 ± 2.9 ng/mg wet weight/day (P Ͻ 0.05, n = 3). In situ mation and hence vein graft failure. Gene transfer to elevzymography revealed a marked inhibition of gelatinolytic ate local levels of tissue inhibitor of metalloproteinases activity by TIMP-2 gene transfer throughout the vein seg-(TIMPs) is therefore a potential treatment. In this study, we ments. Neointima formation and neointimal cell numbers have used lumenal application of a replication-defective were reduced 79% and 71%, respectively (P Ͻ 0.05; recombinant adenovirus to overexpress TIMP-2 and n = 8). TIMP-2 overexpression had no effect on smooth observe the effects on neointimal thickening in a well muscle cell proliferation, secretion of pro-MMP-2 or -9 and characterised human saphenous vein organ culture model.did not inhibit the processing of pro-MMP-2 to its active Increased TIMP-2 expression was localised to lumenal form. Our data indicate that TIMP-2 overexpression surface cells but nevertheless increased total functional reduces neointimal thickening, primarily by inhibiting MMP TIMP-2 secretion after 14 days culture from 4.0 ± 2.0 to activity and hence smooth muscle cell migration.

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Section: Figure 5 Effect Of Radtimp-2 Infection On Neointima Formatiomentioning

confidence: 74%

Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

et al. 1998

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“…In response to vascular injury, VSMC undergo a dramatic change in phenotype -from that of a quiescent / differentiated cell to one that dedifferentiates, proliferates, migrates, re-expresses fetal isoforms of contractile proteins and elaborates extracellular matrix [64][65][66][67]. These features contribute to the development of occlusive vascular diseases such as atherosclerosis, restenosis, and transplant arteriopathy [68,69]. Despite its importance, the molecular mechanisms that control VSMC development and differentiation have yet to be fully elucidated [70].…”

Section: Klfs In Smooth Muscle Biologymentioning

confidence: 99%

Kruppel-like Factors (KLFs) in muscle biology

Haldar¹,

Ibrahim²,

Jain³

2007

Journal of Molecular and Cellular Cardiology

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The Kruppel-like Factor (KLF) family of zinc-finger transcription factors are critical regulators of cell differentiation, phenotypic modulation and physiologic function. An emerging body of evidence implicates an important role for these factors in cardiovascular biology, however, the role of KLFs in muscle biology is only beginning to be understood. This article reviews the published data describing the role of KLFs in cardiomyocytes, smooth muscle cells, and skeletal muscle and highlights the importance of these factors in cardiovascular development, physiology and disease pathobiology.

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“…PDGF has long been recognized as a powerful VSMC mitogen [3] and the induction of PDGF receptors in VSMCs during atherogenesis has been demonstrated in several studies [4,5]. Blockade of PDGF, whether by anti-PDGF antibody [6][7][8], PDGF receptor antisense therapy [9,10], or chimeric knockout in mice [11], reduces lesion formation after vascular injury. Ligand binding to the PDGF receptor causes tyrosine autophosphorylation and Address correspondence to: Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322,, e-mail: kgriend@emory.edu.…”

mentioning

confidence: 99%

Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells

Jay

Papaharalambus

Seidel-Rogol

et al. 2008

Free Radical Biology and Medicine

157

137

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The proliferation of vascular smooth muscle cells is important in the pathogenesis of many vascular diseases. Reactive oxygen species (ROS) produced by NADPH oxidases in smooth muscle cells have been shown to participate in signaling cascades regulating proliferation induced by platelet-derived growth factor (PDGF), a powerful smooth muscle mitogen. We sought to determine the role of Nox5 in the regulation of PDGF-stimulated human aortic smooth muscle cell (HASMC) proliferation. Cultured HASMC were found to express four isoforms of Nox5. When HASMC stimulated with PDGF were pretreated with N-acetyl cysteine (NAC), proliferation was significantly reduced. Proliferation induced by PDGF was also heavily dependent on JAK/STAT activation, as the JAK inhibitor, AG490, was able to completely abolish PDGF-stimulated HASMC growth. Specific knockdown of Nox5 with a siRNA strategy reduced PDGF-induced HASMC ROS production and proliferation. Additionally, siRNA to Nox5 inhibited PDGF-stimulated JAK2 and STAT3 phosphorylation. ROS produced by Nox5 play an important role in PDGF-induced JAK/STAT activation and HASMC proliferation. KeywordsNADPH oxidase; reactive oxygen species; Nox5; vascular smooth muscle cells; proliferation In atherosclerosis and restenosis after percutaneous coronary intervention, cytokines elaborated by both vascular cells and cells invading the vessel wall induce vascular smooth muscle proliferation and contribute to lesion formation. In the normal vessel wall, smooth muscle cells (SMCs) maintain and regulate vascular tone. However, VSMCs change their phenotype to a synthetic, proliferative state when stimulated by a number of different growth factors.One such growth factor, platelet-derived growth factor (PDGF), is expressed by all vascular cell types [1,2] and by invading inflammatory cells, such as monocytes and lymphocytes, in atherosclerosis [1]. PDGF has long been recognized as a powerful VSMC mitogen [3] and the induction of PDGF receptors in VSMCs during atherogenesis has been demonstrated in several studies [4,5]. Blockade of PDGF, whether by anti-PDGF antibody [6][7][8], PDGF receptor antisense therapy [9,10], or chimeric knockout in mice [11], reduces lesion formation after vascular injury. Ligand binding to the PDGF receptor causes tyrosine autophosphorylation and Address correspondence to: Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322,, e-mail: kgriend@emory.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. With regard to PDGF signaling, Nox5 is of particular interest because it...

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Inhibition of Neointimal Smooth Muscle Accumulation After Angioplasty by an Antibody to PDGF

Cited by 1,021 publications

References 32 publications

Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

Kruppel-like Factors (KLFs) in muscle biology

Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells

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