Inhibition of In-Stent Stenosis by Oral Administration of Bindarit in Porcine Coronary Arteries

Abstract

Objective-We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model. Methods and Results-One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1:1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, PϽ0.001, nϭ9 group), neointimal thickness (51%, PϽ0.001), stenosis area (37%, PϽ0.001), and inflammatory score (40%, PϽ0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, PϽ0.05; nϭ6 group) and monocyte/macrophage content (by 55%, PϽ0.01; nϭ5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (PϽ0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10 -300 mol/L) reduced tumor necrosis factor-␣ (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production. Key Words: pharmacology Ⅲ restenosis Ⅲ stent Ⅲ bindarit I ncreasing evidence suggests that monocyte chemotactic protein (MCP)-1/CCL2 plays an early and important role in the formation of intimal hyperplasia and in-stent restenosis 1 by increasing macrophage accumulation and smooth muscle cell (SMC) proliferation and migration. 2,3 Deletion of the MCP-1 gene, blocking MCP-1 signaling or MCP-1 receptor CCR2 decreases neointimal hyperplasia after balloon-and stent-induced injury in several animal models. 4 -7 Similarly, catheter-based adenovirus-mediated antimonocyte chemoattractant gene therapy attenuates in-stent neointimal formation in monkeys. 8 These data suggest that an antiinflammatory/antiproliferative strategy targeting MCP-1 might be an appropriate and reasonable approach for the prevention of neointimal formation and in-stent restenosis. Conclusion-OurBindarit is a selective inhibitor of MCP-1/CCL2, MCP-3/ CCL7, and MCP-2/CCL8 synthesis 9 that shows potent antiinflammatory activity in a number of experimental models, including nephritis, arthritis, pancreatitis, and colitis, 10 -13 as well as reducing myocardial and renal dysfunction in swine renovascular hypertension. 14,15 Phase II clinical trials have shown that bindarit is well tolerated and significantly reduced urinary MCP-1 and albumin excretion in kidney disease. 10,16 Interestingly, we have already shown that oral administration of b...

Monocyte Chemoattractant Protein-1 Levels and Postangioplasty Restenosis of Arteriovenous Fistulas

“…In animal studies, marked upregulation of MCP-1 has been shown in the venous segment of AVFs, and upregulation of MCP-1 gene expression accelerates intimal hyperplasia of vein grafts (7,22). A variety of anti-MCP-1 therapies prevent restenosis in animal studies (23)(24)(25). These data are consistent with our findings and support the concept that MCP-1 itself plays a relevant role in venous intimal hyperplasia of dialysis AVFs.…”

“…In animal studies, neutralization of MCP-1 before or immediately after arterial injury was effective in preventing intimal hyperplasia (24,36,37). Anti-MCP-1 gene therapy had been shown to inhibit smooth muscle cell proliferation and vein-graft thickening (23,25).…”

Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models

“…The effects of bindarit are mediated by the down-regulation of the classical NF-kB signaling pathway, which involves reduction in IkBa and p65 phosphorylation and reduced activation of NF-kB dimers, and the subsequently reduced nuclear translocation and DNA-binding of p65 [17]. In vivo, the therapeutic effects of bindarit in a number of experimental models of inflammatory diseases, including nephritis, arthritis, pancreatitis, colitis and vascular damage, have been associated with its ability to inhibit MCP-1 production and selectively interfere with monocyte/macrophage recruitment and the early inflammatory response [18][19][20][21][22][23][24][25]. Furthermore, studies in human-melanoma-bearing mice, in which the MCP-1-overexpressing melanoma cells are subcutaneously injected into nude mice, have indicated that bindarit can reduce tumor growth and macrophage recruitment through inhibition of MCP-1 [26].…”

Renal accumulation of macrophages in experimental polycystic kidney disease is reduced by bindarit

“…Bindarit is devoid of any immunosuppressive activity and of effects on arachidonic acid metabolism [10] . This molecule exerted potent anti-inflammatory effects in several experimental diseases, such as arthritis [12] , pancreatitis [13] , coronary in-stent stenosis [14] . In mice with lupus nephritis bindarit reduced MCP-1 upregulation, limited the infiltration of macrophages in the kidney, retarded the development of proteinuria and renal damage, and prolonged animal survival [15,16] .…”