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Inhibition of Matrix Deposition: A New Strategy for Prevention of Restenosis After Balloon Angioplasty

Backes, Andreas MD*; Seay, Ulrike*; Sedding, Daniel G MD*; Tillmanns, Harald H MD*; Braun-Dullaeus, Ruediger C MD

Journal of Cardiovascular Pharmacology: February 2010 - Volume 55 - Issue 2 - p 213-218
doi: 10.1097/FJC.0b013e3181ce97f6
Original Article
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Restenosis after balloon angioplasty or stent placement is characterized by local accumulation of mainly vascular smooth muscle cells and the synthesis of extracellular matrix molecules (ECM). We hypothesized that inhibition of ECM synthesis represents a strategy to prevent trauma-induced neointima formation. Rats were treated with pirfenidone (1 g/kg of body weight orally.), an inhibitor of growth factor-induced collagen synthesis, and subjected to balloon denudation of the carotid artery. Two weeks later, computer-aided morphometry was done and compared with untreated controls (each n = 6). Neointimal proliferative activity was quantified immunohistochemically by counting PCNA-positive nuclei, and collagen deposition was visualized by picrosirius red staining and semi-quantified by Northern blot. Control-injured animals developed marked neointimal thickening within 2 weeks (I/M, mean intima to media ratio: 2.42 ± 0.15) resulting in an 89.2% luminal narrowing. The neointima mainly consisted of vascular smooth muscle cells embedded in collagen. Neointima formation was strongly reduced when balloon-injured animals had been treated with pirfenidone (I/M ratio 0.22 ± 0.08, P < 0.001), resulting in a minimal residual narrowing of the lumen (7.9%). I/M ratio did not further increase even after discontinuation of the drug for 14 days (0.35 ± 0.13). Proliferative activity within the neointima was unaffected by the drug, 4.4% versus 4.8% of neointimal cells stained positive for PCNA in carotid arteries of treated versus untreated animals, respectively. However, picrosirius red staining demonstrated marked attenuation of collagen deposition, a finding that was further confirmed by Northern blot of homogenized vessels. Pirfenidone, currently being investigated clinically for the treatment of various fibrotic diseases, is able to prevent neointimal lesion formation most likely through inhibition of local ECM deposition. Targeting matrix deposition may have an intriguing potential for the prevention of vascular proliferative diseases.

From the *Internal Medicine, Department of Cardiology, Giessen University, Giessen, Germany; and †Internal Medicine, Department of Cardiology, Angiology and Pneumology, Magdeburg University, Magdeburg, Germany.

Received for publication August 17, 2009; accepted December 8, 2009.

Supported by grants from the Deutsche Forschungsgemeinschaft (BR 1603/4, SFB655/A11, and Deutsche Forschungsgemeinschaft Research Center for Regenerative Therapies). Pirfenidone was a generous gift of Dr Margolin, Marnac, Inc.

The authors report no conflicts of interest.

Reprints: Ruediger C. Braun-Dullaeus, MD, Internal Medicine, Department of Cardiology, Angiology and Pneumology, Magdeburg University, Leipziger Straße 44, 39120 Magdeburg (e-mail: r.braun-dullaeus@med.ovgu.de).

© 2010 Lippincott Williams & Wilkins, Inc.