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Published as doi: 10.1096/fj.08-114173.
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(The FASEB Journal. 2009;23:557-564.)
© 2009 FASEB

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

Thomas S. Monahan, Nicholas D. Andersen1, Michelle C. Martin, Junaid Y. Malek, Gautam V. Shrikhande, Leena Pradhan, Christiane Ferran and Frank W. LoGerfo

Department of Surgery, Division of Vascular Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

1Correspondence: Beth Israel Deaconess Medical Center, 4 Blackfan Cir., HIM Bldg., Rm. 131, Boston, MA 02115, USA. E-mail: nicholas.andersen{at}duke.edu

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 p27kip1. 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.—Monahan, T. S., Andersen, N. D., Martin, M. C., Malek, J. Y., Shrikhande, G. V., Pradhan, L., Ferran, C., LoGerfo, F. W. MARCKS silencing differentially affects human vascular smooth muscle and endothelial cell phenotypes to inhibit neointimal hyperplasia in saphenous vein.


Key Words: bypass graft • RNA interference • small interfering RNA • gene therapy • transfection • protein kinase C






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