Molecular Basis of Restenosis and Drug-Eluting Stents

Costa, Marco A.; Simon, Daniel I.

doi:10.1161/01.cir.0000163587.36485.a7

Cited by 453 publications

(384 citation statements)

References 220 publications

(141 reference statements)

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“…More than one third of these procedures will have limited durability owing to the formation of intimal hyperplasia, the pathological response of a blood vessel to injury. Although there is no therapy to prevent intimal hyperplasia in bypass grafts, there are some strategies to prevent intimal hyperplasia after angioplasty and stenting 2. The current antiproliferative agents used to prevent intimal hyperplasia formation inhibit both smooth muscle cell and endothelial cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

Makkar

Strickland

et al. 2015

JAHA

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BackgroundTranscription of the myristoylated alanine‐rich C kinase substrate (MARCKS) is upregulated in animal models of intimal hyperplasia. MARCKS knockdown inhibits vascular smooth muscle cell (VSMC) migration in vitro; however, the mechanism is as yet unknown. We sought to elucidate the mechanism of MARCKS‐mediated motility and determine whether MARCKS knockdown reduces intimal hyperplasia formation in vivo.Methods and Results MARCKS knockdown blocked platelet‐derived growth factor (PDGF)‐induced translocation of cortactin to the cell cortex, impaired both lamellipodia and filopodia formation, and attenuated motility of human coronary artery smooth muscle cells (CASMCs). Activation of the small GTPases, Rac1 and Cdc42, was prevented by MARCKS knockdown. Phosphorylation of MARCKS resulted in a transient shift of MARCKS from the plasma membrane to the cytosol. MARCKS knockdown significantly decreased membrane‐associated phosphatidylinositol 4,5‐bisphosphate (PIP 2) levels. Cotransfection with an intact, unphosphorylated MARCKS, which has a high binding affinity for PIP 2, restored membrane‐associated PIP 2 levels and was indispensable for activation of Rac1 and Cdc42 and, ultimately, VSMC migration. Overexpression of MARCKS in differentiated VSMCs increased membrane PIP 2 abundance, Rac1 and Cdc42 activity, and cell motility. MARCKS protein was upregulated early in the development of intimal hyperplasia in the murine carotid ligation model. Decreased MARKCS expression, but not total knockdown, attenuated intimal hyperplasia formation.Conclusions MARCKS upregulation increases VSMC motility by activation of Rac1 and Cdc42. These effects are mediated by MARCKS sequestering PIP 2 at the plasma membrane. This study delineates a novel mechanism for MARCKS‐mediated VSMC migration and supports the rational for MARCKS knockdown to prevent intimal hyperplasia.

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Section: Introductionmentioning

confidence: 99%

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

Makkar

Strickland

et al. 2015

JAHA

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“…Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention [1]. Accumulating evidence now shows that inflammatory cell infiltration [2,3], proliferation/migration of vascular smooth muscle cells (VSMCs) [4,5], and deposition of extracellular matrix [6] all contribute to the pathogenesis of neointimal hyperplasia.…”

Section: Introductionmentioning

confidence: 99%

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Yang

Sakurai

Kamiyoshi

et al. 2013

Journal of Molecular and Cellular Cardiology

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Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene.Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule.We compared the effect of CGRP deficiency on neointima formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointima formation after vascular injury was markedly enhanced in CGRP-/-mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointima formation in CGRP-/-mice. In vitro analysis showed CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease.

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“…In addition to endothelial dysfunction and inflammation, proliferation of smooth muscle cells (SMC) 3 is considered to play a pivotal role in the pathogenesis of atherosclerosis and the failure of interventional approaches used to treat related occlusive vascular complications (2)(3)(4). With the evolving understanding of the mechanisms contributing to the development of vascular diseases, members of the nuclear hormone receptor superfamily of transcription factors have emerged as key transcriptional regulators of inflammation and cell proliferation (5,6).…”

mentioning

confidence: 99%

The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell Proliferation

Nomiyama

Nakamachi

Gizard

et al. 2006

Journal of Biological Chemistry

117

150

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Members of the nuclear hormone receptor superfamily function as key transcriptional regulators of inflammation and proliferation in cardiovascular diseases. In addition to the ligand-dependent peroxisome proliferator-activated receptors and liver X receptors, this family of transcription factors includes a large number of orphan receptors, and their role in vascular diseases remains to be investigated. The neuron-derived orphan receptor-1 (NOR1) belongs to the ligand-independent NR4A subfamily, which has been implicated in cell proliferation, differentiation, and apoptosis. In this study, we demonstrate NOR1 expression in vascular smooth muscle cells (SMC) of human atherosclerotic lesions. In response to mitogenic stimulation with platelet-derived growth factor (PDGF), SMC rapidly express NOR1 through an ERK-MAPK-dependent signaling pathway. 5-Deletion analysis, site-directed mutagenesis, and transactivation experiments demonstrate that PDGF-induced NOR1 expression is mediated through a cAMPresponse element-binding protein (CREB)-dependent transactivation of the NOR1 promoter. Consequently, short interfering RNAmediated depletion of CREB abolished PDGF-induced NOR1 expression in SMC. Furthermore, PDGF induced Ser-133 phosphorylation of CREB and subsequent binding to the CRE sites of the endogenous NOR1 promoter. Functional analysis demonstrated that PDGF induces NOR1 transactivation of its consensus NGFI-B-response elements (NBRE) in SMC. We finally demonstrate that SMC isolated from NOR1-deficient mice exhibit decreased cell proliferation and characterize cyclin D1 and D2 as NOR1 target genes in SMC. These experiments indicate that PDGF-induced NOR1 transcription in SMC is mediated through CREB-dependent transactivation of the NOR1 promoter and further demonstrate that NOR1 functions as a key transcriptional regulator of SMC proliferation.Atherosclerosis, the subsequent development of occlusive vascular diseases, and the failure of treatment approaches such as postangioplasty restenosis involve several interrelated processes (1, 2). In addition to endothelial dysfunction and inflammation, proliferation of smooth muscle cells (SMC) 3 is considered to play a pivotal role in the pathogenesis of atherosclerosis and the failure of interventional approaches used to treat related occlusive vascular complications (2-4). With the evolving understanding of the mechanisms contributing to the development of vascular diseases, members of the nuclear hormone receptor superfamily of transcription factors have emerged as key transcriptional regulators of inflammation and cell proliferation (5, 6). Based on this evidence, elucidation of the molecular pathways utilized by nuclear receptors to regulate programs of gene expression is expected to facilitate the development of novel pharmacological approaches for the treatment of cardiovascular diseases. Nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) subfamilies are expressed in SMC and inhibit their proliferation in response ...

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Molecular Basis of Restenosis and Drug-Eluting Stents

Cited by 453 publications

References 220 publications

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell Proliferation

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