Controlled release of small interfering RNA targeting midkine attenuates intimal hyperplasia in vein grafts

Abstract

These results suggest that midkine is a candidate molecular target for preventing vein graft failure. Furthermore, for clinical applications of siRNA, a single intraoperative atelocollagen-based nonviral delivery method could be a reliable approach to achieve maximal function of siRNA in vivo. This strategy may be a useful and practical form of gene therapy against human vein graft failure.

Emerging Epigenetic Therapy for Vascular Proliferative Diseases

“…The involvement of CCN1, an extracellular matrix-associated protein, in the development of neointimal hyperplasia is confirmed by siRNA-mediated knockdown approach (Matsumae et al, 2008). The atheroprotective role of midkine (MK), a heparin-binding growth factor, is corroborated by the use of MK-siRNA (Banno, et al, 2006). NADPH oxidase has a critical role in the development of neointimal hyperplasia and restenosis due to its contribution to oxidative stress, which is blocked by siRNA specific to NOX2 gene Cybb, an important component of NADPH oxidase (J.M.…”

“…These include antisense oligonucleotides (ODNs), short segments of RNA with enzymatic activity (ribozymes) and small interfering RNAs [siRNA] (Dzau et al, 2002;J.M. Li et al, 2010;Banno, et al, 2006). A number of studies have shown that gene therapies can be targeted for reducing cholesterol levels, inflammation and thrombosis (Feldman & Isner, 1995); for upregulating apo-A1 and downregulating chemoattractant protein-1 (MCP1)receptor expression (Tangirala, 1999); transferring pleiotropic atheroprotective nitric oxide synthase [NOS] (Qian, 1999); targeting vascular redox biology through heme oxygenase-1, superoxide dismutase, catalase and glutathione peroxidase antioxidant gene therapy to attenuate oxidative stress (Van Assche, 2011); and lipid-lowering gene therapy to reduce plasma LDL levels (Grossman et al, 1995).…”

“…Importantly, delivery of antiproliferative genes such as those coding for p21Cip1, p27Kip1, and iNOS are used to inhibit stenosis and neointimal hyperplasia (Dzau et al, 2002;Von der Leyen & Dzau, 2001]. Conversely, silencing the genes that contribute to proliferation via antisense ODNs (Dzau et al, 2002;Khanna, 2008;Kishore & Losordo, 2007;Gaffney et al, 2007;Melo et al, 2005) or siRNA approach is also effective in preventing in-stent and graft neointimal hyperplasia (Banno, et al, 2006;F. Li et al, 2005; J.M.…”

“…Antisense ODNs-based inhibition of cell proliferation-related genes such as PCNA, c-myc, c-myb or different cyclin-dependent kinases (cdks) have been successfully carried out in experimental models of vascular lesion formation (Braun-Dullaeus et al, 1998;Dzau et al, 2002;Morishita et al, 1993;Simons et al, 1994). RNA interference (RNAi) technology is becoming popular approach to alter gene expressions to interrogate their role in pathogenesis of disease, which has utility in the inhibition of VSMC proliferation and neointimal hyperplasia (Banno, et al, 2006;F. Li et al, 2005; J.M.…”

In vitro and in vivo suppression of hepatocellular carcinoma growth by midkine-antisense oligonucleotide-loaded nanoparticles

“…The antisense oligonucleotide (ASODN) that targets MK has been reported to suppress the growth of tumors in nude mice [11,12] . Additionally, www.wjgnet.com siRNA or an ASODN that targets MK inhibits neointima formation [13] and renal injury after ischemia [14] . MK has been suggested to play an important role in carcinogenesis, thus MK can serve as a novel tumor marker or therapeutic target.…”