Inhibition of in-stent restenosis by oral copper chelation in porcine coronary arteries

Abstract

.-Stress-induced release of IL-1␣ and fibroblast growth factor-1 is dependent on intracellular copper and is a major driver of neointimal hyperplasia. Therefore, we assessed the effect of tetrathiomolybdate (TTM), a clinically proven copper chelator, on in-stent restenosis. Nine pigs were treated with TTM (5 mg/kg po) twice daily for 2 wk before stent implantation and for 4 wk thereafter, and nine pigs served as controls. In-stent restenosis was assessed by quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), and histomorphometry. Serum ceruloplasmin activity was used as a surrogate marker of copper bioavailability. In TTM-treated animals, ceruloplasmin dropped 70 Ϯ 10% below baseline levels. Baseline characteristics were comparable in TTM-treated and control animals. At 4-wk follow-up, all parameters relevant to in-stent restenosis were significantly reduced in TTM-treated animals: minimal lumen diameter by QCA was 2.03 Ϯ 0.57 and 1.47 Ϯ 0.45 mm in TTM-treated and control animals, respectively (P Ͻ 0.05), percent stenosis diameter was 39% less in TTM-treated animals (27.1 Ϯ 16.6% vs. 44.5 Ϯ 16.1%, P Ͻ 0.05), minimal lumen area by IVUS was 60% larger in TTM-treated animals (4.27 Ϯ 1.56 vs. 2.67 Ϯ 1.19 mm 2 , P Ͻ 0.05), and neointimal volume by histomorphometry was 37% less in TTM-treated animals (34.9 Ϯ 11.5 vs. 55.2 Ϯ 19.6 mm 3 , P Ͻ 0.05). We conclude that systemic copper chelation with a clinically approved chelator significantly inhibits in-stent restenosis.inflammation; stent RESTENOSIS AFTER PERCUTANEOUS coronary intervention is an inflammation-driven process that results in the formation of neointima at the site of injury, and it can affect up to 50% of patients who undergo this procedure. IL-1 is a strong contributor to the development of restenosis (5, 15) through induction and nuclear translocation of NF-B (23) and increased expression of platelet-derived growth factor and fibroblast growth factor (FGF) (9), and, most notably, IL-1␣ can recruit and activate macrophages, which are the richest cellular source of growth factors in the body (4). Indeed, there is a direct correlation between inflammatory cell infiltration and neointimal formation at the site of vascular intervention (18).Besides inflammatory cytokines, proliferative factors are important determinants of neointimal proliferation. One of them, FGF-1, shares a significant tertiary structural homology with IL-1␣ and, similar to IL-1␣, lacks a signal sequence for endoplasmic reticulum Golgi-dependent secretion (20). It has been shown that FGF-1 can be a very potent inducer of intimal hyperplasia through its mitogenic activity (19), stimulation of cell migration (12), and promotion of adventitial angiogenesis in the injured vessel wall (19). Importantly, stress-induced release of FGF-1 and IL-1␣ requires the copper chaperone S100A13 for the intracellular assembly of the components of their release complexes (24, 28), and this process is strictly copper dependent (14, 17). As shown recently, copper suppression blocks the stres...

Secretion without Golgi

“…Additionally, TM downregulates the number of macrophages, as well as FGF1, S100A13, and IL1α levels in carotid artery walls. It was also found that TM inhibits in‐stent restenosis in porcine coronary arteries [Mandinov et al, 2006], These data suggest that inhibition of the non‐classical release of FGF1 and IL1α by Cu 2+ chelation may represent a promising approach to the management of restenosis. More recently, it was demonstrated that in rats TM blocks the development of antigen‐induced arthritis, a pathology that involves IL1 [Omoto et al, 2005].…”

Do Statins have a Role in Reduction/Prevention of Post‐PCI Restenosis?

“…CP contains copper, and accounts for 95% of the total circulating copper in adults. The copper chelator tetrathiomolybdate (TTM) given twice daily for 2 weeks before coronary stent implantation in pigs, and for 4 weeks thereafter, reduced the extent of restenosis by 39%, and this effect was associated with a reduction of 70% in serum CP [238]. In another study, Mandinov et al [239] reported that TTM treatment produced a 60% reduction in neointimal hyperplasia in balloon injured carotid artery in rats.…”

Evaluation of promoting effect of a novel Cu-bearing metal stent on endothelialization process from in vitro and in vivo studies

“…Mandinov et al . also found that ISR could be inhibited directly by oral copper chelation in porcine coronary 27 . Thus, the beneficial influence of Cu ions on reduction of ISR was well recognized in the coronary field.…”