Intimal hyperplasia (IH) may be the leading cause of late vein

Intimal hyperplasia (IH) may be the leading cause of late vein and prosthetic bypass graft failure. IH. Several studies have been performed in this direction to target genes that are involved in IH. In this review we discuss siRNA targets that are being GNE-7915 investigated for prevention and treatment of IH. Introduction GNE-7915 Intimal hyperplasia (IH) Intimal hyperplasia remains the most common cause of cardiovascular bypass graft failure and can also occur after angioplasty. IH is the result of an excessive wound healing response of the layers of the arterial or venous vessel wall. The end product is an accumulation of synthetic smooth muscle cells and extracellular matrix in the lumen of the vessel. These processes lead to a successive narrowing of the vessel lumen thus impairing blood flow. Several origins of these activated smooth muscle cells have been discussed which include media adventitia and bone marrow precursor cells (Davies and Hagen 1994 Goel and and mitigated IH in a rat model of jugular vein-to-carotid artery GNE-7915 interposition grafting (Wang after ligation injury increased Ptc-1/Notch expression VSMC growth and vascular remodeling. Ptc-1 silencing by perivascular siRNA delivery blocked these effects (Redmond (Monahan et al. 2007 Miscellaneous Na Channel Na(V)1.7 – SCN9A Voltage-gated Na(+) channel currents (I(Na)) are expressed in several types of SMC. Na(V)1.7 is also expressed in aortas after balloon injury. Different from native aorta cultured aortic SMCs expressed SCN9A which encodes for Na(V)1.7. SCN9A silencing inhibited cell migration while not affecting cell proliferation (Meguro et al. 2009 TSP-2 Thrombospondin-2 GNE-7915 (TSP-2) is an antiangiogenic matricellular protein that is upregulated in neointimal smooth muscle cells GNE-7915 after prosthetic arterial bypass graft placement. TSP-2 silencing led to increased HAoSMC attachment to fibronectin in vitro (Yoshida et al. 2011 TSP-2 silencing could be achieved in AoSMC that infiltrated polyethyleneimine-TSP-2-siRNA-coated electrospun Dacron graft materials (Nabzdyk et al. 2014 Girdin Actin-binding protein girdin Rabbit Polyclonal to PHF1. is upregulated in injured vein grafts and has previously linked to arterial remodeling. In a rabbit vein graft model perivascular girdin siRNA delivery mitigated IH. Further girdin silencing in SMC reduced cell migration and proliferation illustrating girdin’s relevant role in actin filament rearrangement (Miyachi et al. 2013 G protein-coupled receptor alpha-q (Galphaq) G protein-coupled receptors are involved in IH formation in parts by enhancing SMC proliferation. Galphaq increases vascular smooth muscle cell proliferation in vitro. In a murine femoral artery wire injury model Galphaq expression increased in a time-dependent manner. Galphaq siRNA applied externally to injured mouse femoral arteries reduced SMC proliferation but not cell migration. Galphaq silencing also reduced IH development and temporarily decreased MMP-9 but not GNE-7915 MMP-2 expression (Zou et al. 2013 Rab5a Rab5a a member of the Rab family of GTPases and key regulator of clathrin endosome formation is upregulated in rat anastomotic IH lesions. Rab5a silencing reduced proliferation and migration of rat thoracic aorta VSMC (Ma et al. 2010 Human antigen R (HuR) HuR is an RNA-binding protein of the HU/ELAV family that stabilizes various mRNAs including those of growth factors cell cycle regulators and cytokines. Elevated levels of HuR have been detected in neointimal lesions. HuR silencing decreased basal and platelet-derived growth factor (PDGF) stimulation of VSMC proliferation (Pullmann et al. 2005 Conclusion Similar to atherosclerosis IH has been a tremendous challenge for the field of vascular biology inflicting an enormous disease and financial burden on patients and the health care system respectively. To date no effective pharmacologic strategy has been developed to sufficiently ameliorate IH formation after bypass grafting. Drug eluting stents (DES) for coronary angioplasty have been used for over a decade (Bangalore et al. 2012 DES release immunosuppressive compounds such as sirolimus and everolimus (inhibit mTOR pathway) or mitosis inhibitors such a paclitaxel (Bangalore et al. 2012 While these devices have shown to reduce IH formation after angioplasty this harsh ablative approach renders patients at high risk for instent thrombosis. These patients are thus placed.