Published Online
on July 18, 2005

A more recent version of this article appeared on July 26, 2005

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Submitted on September 27, 2004
Revised on March 29, 2005
Accepted on April 12, 2005

Biliverdin Administration Prevents the Formation of Intimal Hyperplasia Induced by Vascular Injury

Atsunori Nakao MD, Noriko Murase MD, Chien Ho PhD, Hideyoshi Toyokawa MD, Timothy R. Billiar MD, and Shinichi Kanno MD^*

From the Thomas E. Starzl Transplantation Institute (A.N., N.M., H.T.) and Department of Surgery (T.R.B., S.K.), University of Pittsburgh, Pittsburgh, Pa, and the NMR Center, Carnegie Mellon University (C.H.), Pittsburgh, Pa.

^* To whom correspondence should be addressed. E-mail: shk34{at}pitt.edu.

Background--Autologous vein grafts and balloon angioplasty are still commonly used for arterial reconstructive procedures. Their success is limited by the development of intimal hyperplasia (IH). Biliverdin (BVD), one of the by-products of heme degradation, has been shown to have potent antioxidant and antiinflammatory effects. We hypothesized that BVD administration would protect vascular tissue against vascular injury.

Methods and Results--The effects of BVD administration against IH after vascular injury were analyzed in an arterialized vein graft model and a balloon injury model in rats. BVD treatment significantly suppressed the development of IH in both models compared with those without BVD. The mechanisms by which BVD treatment inhibits IH development might include decreasing c-Jun NH₂ terminal kinase activation and preventing apoptosis of endothelial cells. BVD also suppressed vascular smooth muscle cell migration in vitro.

Conclusions--BVD administration prevented IH associated with arterialized vein graft vasculopathy or balloon angioplasty-induced vessel injury. These results suggest that a treatment regimen with exogenous BVD administration could provide an effective therapeutic adjunct to facilitate transfer of experimental treatments for vascular injury to the clinic.

Key words: angioplasty • antioxidants • apoptosis • reperfusion • restenosis

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