Metalloproteinase Inhibition and the Response to Angioplasty and Stenting in Atherosclerotic Primates

Abstract

Abstract-Determinants of restenosis after angioplasty include constrictive remodeling and intimal hyperplasia. Both processes require extensive matrix turnover, so matrix metalloproteinases (MMPs) have become potential targets of antirestenosis therapies. We studied the effects of RO113-2908, a broad-spectrum MMP inhibitor (MMPI), on the response to iliac artery angioplasty and stenting in atherosclerotic cynomolgus monkeys. Lumen diameter (LD) was measured angiographically, and artery wall geometry was assessed after perfusion-fixation at 4 weeks. Angiogenesis was measured in subcutaneous polyvinyl alcohol disks. Key Words: restenosis Ⅲ constrictive remodeling Ⅲ metalloproteinases Ⅲ angioplasty Ⅲ stents E ach year, Ϸ3 million patients undergo reconstruction of atherosclerotic arteries, and many subsequently develop recurrent stenoses at the sites of repair. Restenosis after angioplasty or stenting is due primarily to constrictive artery wall remodeling or intimal hyperplasia, respectively. These processes involve extensive reorganization of extracellular matrix to facilitate changes in artery wall geometry and accumulation of new intimal mass.Matrix degradation is tightly regulated in the normal artery wall through a balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors (eg, TIMPs). Atherosclerosis shifts the balance toward degradation, as MMPs are produced by accumulating macrophages and activated smooth muscle cells (SMCs). 1-3 Angioplasty further increases MMP production, 4 -7 and matrix turnover and maturation continue for months after angioplasty in all layers of the arterial wall, likely contributing to SMC proliferation, migration, and remodeling. 7-9 These observations have led to speculation that inhibiting MMP activity could limit restenosis. However, experiments with MMP inhibitors to prevent intimal hyperplasia in animal models have shown mixed results, and effects on remodeling have not been well characterized. 5,6,10 -13 Whether this approach can improve the response to angioplasty or stenting in human beings with advanced atherosclerosis is yet to be defined.To extend this approach to a preclinical model, we treated atherosclerotic cynomolgus monkeys with a broad-spectrum MMPI for 4 weeks after angioplasty and stent-angioplasty to determine the impact on restenosis. Treatment provided continuous, systemic MMP inhibitory activity and inhibited angiogenesis, but artery wall remodeling and intimal hyperplasia were not improved. Additional preclinical research is needed to define the spectrum of matrix-degrading proteases critical in constrictive remodeling and intimal hyperplasia of atherosclerotic arteries after angioplasty. Methods Animal ModelThirty-one adult male monkeys (Macaca fascicularis; mean age, 13.5 years) consumed an atherogenic diet (0.28 mg cholesterol/kcal) for 2.5Ϯ0.1 years to induce advanced iliac artery lesions. 8,14 -17 Animals were then randomized into MMPI (nϭ16) or control (nϭ15) groups based on diet duration and the ratio of total to HDL choleste...

Metalloproteinase inhibitors: biological actions and therapeutic opportunities

“…However, small molecule MMP inhibitors fail to prevent restenosis, even though they efficiently block early smooth muscle cell migration (Bendeck et al, 1996). Recently, the broad spectrum MP inhibitor RO113-2908 failed to prevent angioplasty-or stent-induced intermal hyperplasia over 4 weeks in atherosclerotic primates (Cherr et al, 2002), although MP inhibitors do reduce constrictive remodeling in a porcine angioplasty model (de Smet et al, 2000). Similarly, TIMP overexpression (Cheng et al, 1998;Dollery et al, 1999;Forough et al, 1996) prevented smooth muscle cell migration but long-term benefits were not fully established.…”

A Matrix Metalloproteinase Inhibitor, ONO-4817, Suppresses the Development of Aortic Intimal Hyperplasia in Experimental Hyperlipidemic Rabbit

“…7,8) We herein have shown that ONO-4817 could inhibit the atherosclerotic neointimal hyperplasia in experimental hyperlipidemic rabbits.…”

“…In previous studies 7,8) and a recent study by RS-130830, 9) it was reported that intimal hyperplasia could not be attained by these drugs. The inhibitory activity of RS-130830 and ONO-4817 is summarized in Table. 9,10) The balance of inhibitory activity, not the strength of inhibitory activity, may explain the inhibition of intimal hyperplasia.…”

“…7,8) Because ONO-4817 may be the first MMPi that is able to suppress the development of intimal hyperplasia induced by intimal injury in hypercholesterolemic hamsters, 16) we have presented data on atherosclerotic intimal hyperplasia in dietary hypercholesteloremic rabbits in this report.…”

“…[4][5][6] Several studies with synthetic matrix metalloproteinase inhibitors (MMPi) have been conducted to test this hypothesis, but no convincing morphologic data have yet been obtained. [7][8][9] ONO-4817, a newly synthesized MMPi, is active as an MMPi after oral administration, and has a partially selective inhibitory spectrum (MMP-2, MMP-8, MMP-9, MMP-12, and MMP-13 but not MMP-1 or MMP-7).…”