Temporal gene expression following prosthetic arterial grafting1

Willis, David J.; Kalish, Jeffrey; Li, Cheng; Deutsch, E; Contreras, Mauricio; LoGerfo, Frank W.; Quist, William C.

doi:10.1016/j.jss.2003.12.014

Cited by 21 publications

(19 citation statements)

References 41 publications

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“…MARCKS protein expression is significantly increased at the early phase of intimal hyperplasia in the mouse carotid ligation model. This finding confirms the previously noted association between active MARCKS transcription and development of intimal hyperplasia after bypass surgery in large mammals 16, 17, 39. Genetically disrupting 1 allele of the MARCKS gene is sufficient to block protein upregulation of MARCKS in the carotid artery in response to ligation and prevents intimal hyperplasia formation.…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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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“…We previously found MARCKS transcription to be up-regulated in canine models of IH (9,10). Here, we employ a siRNA-mediated loss-of-function approach to further explore the contribution of MARCKS to IH.…”

Section: Discussionmentioning

confidence: 99%

“…To gain insight into the molecular signals responsible for IH, we previously performed microarray studies of prosthetic and vein graft IH in a canine model (9,10). This analysis identified genes that were up-regulated or down-regulated at discrete time points after creation of the bypass graft.…”

mentioning

confidence: 99%

MARCKS silencing differentially affects human vascular smooth muscle and endothelial cell phenotypes to inhibit neointimal hyperplasia in saphenous vein

et al. 2008

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Intimal hyperplasia (IH) limits the patency of all cardiovascular vein bypass grafts. We previously found the myristoylated alanine-rich C kinase substrate (MARCKS), a key protein kinase C (PKC) substrate, to be up-regulated in canine models of IH. Here, we further characterize the role of MARCKS in IH and examine the phenotypic consequences of MARCKS silencing by small interfering RNA (siRNA) transfection in human vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) in vitro and use a rapid 10-min nonviral siRNA transfection technique to determine the effects of MARCKS silencing in human saphenous vein cultured ex vivo. We demonstrate MARCKS silencing attenuates VSMC migration and arrests VSMC proliferation in part through the up-regulation of the cyclin-dependent kinase inhibitor p27(kip1). Conversely, MARCKS silencing had little or no effect on EC migration or proliferation. These phenotypic changes culminated in reduced neointimal formation in cultured human saphenous vein. These data identify MARCKS as a pathogenic contributor to IH and indicate therapeutic MARCKS silencing could selectively suppress the "atherogenic," proliferative phenotype of VSMCs without collateral harm to the endothelium. This approach could be readily translated to the clinic to silence MARCKS in vein bypass grafts prior to implantation.

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“…Accordingly, cephalic vein graft remodelling and distal anastomosis of prosthetic arterial grafts were studied in dogs [15,16]. Several collagens were upregulated, and smoothelin, which is a marker of SMC contractile phenotype, was downregulated during the vein graft remodelling.…”

Section: Microarray Analysis Of Atherosclerotic Lesionsmentioning

confidence: 99%