meta-Iodobenzylguanidine, an Inhibitor of Arginine-Dependent Mono(ADP-ribosyl)ation, Prevents Neointimal Hyperplasia

Abstract

The association of ADP-ribosylation with cell proliferation and ischemia-reperfusion injury suggests that it may be a suitable target for therapeutic control of revascularization-induced injury. The purpose of this study was to investigate the inhibitory actions of ADP-ribosylation inhibitors on restenosis. In organ culture, the poly(ADP-ribose) polymerase (PARP) inhibitor 3,4-dihydro-5-methylisoquinolinone (PD128763) was unable to prevent neointimal hyperplasia, whereas the arginine-dependent mono(ADP-ribosyl)transferase (ART) inhibitor meta-iodobenzylguanidine (MIBG) was highly effective (EC 50 21 M). Treatment with 3-aminobenzamide (3AB), a less potent ART inhibitor, also produced a significant reduction in neointimal hyperplasia. Single doses (25 mM) of MIBG and 3AB were also applied within a fibrin coagulum directly to the adventitial surface of the porcine femoral artery after balloon catheter injury in vivo. MIBG reduced the neointimal index, measured 14 days after angioplasty, by 82%, whereas 3AB was ineffective. However, when extended to 45 days, the neointimal index was not significantly decreased by MIBG treatment relative to control. Assessment of MIBG release from the fibrin glue showed that the bulk of the compound was eluted within 3 days, suggesting that the vehicle was not suitable for long-term delivery. On the other hand, direct infusion of MIBG into vessels was able to reduce neointimal hyperplasia over 14 days in organ culture. These data support the conclusion that the cellular retention characteristics of MIBG contribute significantly to the efficacy of this compound. Based on these results, ART, but not PARP, may be a credible target for therapeutic treatment of restenosis.Revascularization procedures, such as balloon angioplasty, stenting, and bypass graft surgery, were developed for the treatment of coronary and peripheral arterial disease. These procedures effectively alleviate the symptoms that result from an arterial obstruction due to atherosclerosis (e.g., angina and claudication) and improve quality of life for these patients. Traditionally, the long-term efficacy of these procedures has been limited by restenosis, a reduction of the vascular lumen at the site of intervention. Restenosis rates of 20 to 50% were associated with balloon angioplasty and bare metal stents; however, the introduction of drug-eluting stents (DES) has reduced the incidence of restenosis to Ͻ10%

Effect of ART1 on the proliferation and migration of mouse colon carcinoma CT26 cells in vivo

“…Yau et al (6) hypothesized that mono-ADP-ribosylation enzymes may be associated with the progression of gastric cancer. A previous study (11) has shown that ART1 expression was increased in colorectal cancer and has a positive correlation with the expression of vascular endothelial growth factor (VEGF), which suggests that it may have an association with tumor angiogenesis.…”

“…In the epithelial cells of the respiratory tract and the bronchoalveolar lavage fluid of people with asthma, ART1 may catalyze the mono-ADP-ribosylation of human neutrophil peptide-1 (3), resulting in an inflammatory response. Yau et al (5) demonstrated that meta-iodobenzylguanidine (MIBG), a selective inhibitor of arginine-specific mono-ADP-ribosylation (6), is able to suppress the proliferation and differentiation of vascular smooth muscle cells. The researchers hypothesized that mono-ADP-ribosylation is involved in a Rho-dependent signaling pathway.…”

Fibrin glue as a drug delivery system

“…In a study by Yau et al[44] meta-iodobenzylguanidine (MIBG) was loaded into a fibrin gel for long-term release. MIBG inhibits arginine dependent mono(ADP-ribosyl)ation and might prevent neointimal hyperplasia after angioplasty.…”

Application of materials as medical devices with localized drug delivery capabilities for enhanced wound repair

“…Materials used in surgical glues, such as fibrin glue, albumin and urethane, can rapidly form a rigid, hardened structure and also demonstrate good biocompatibility [187–189]. Among the available options, fibrin glue has been widely investigated as a carrier for drugs, biological factors, or genes [190–194]. Due to its high water uptake and pore-forming abilities, fibrin glue has additionally been studied in the form of tissue engineering scaffolds [195–197].…”