Published Online
on September 29, 2003

A more recent version of this article appeared on October 28, 2003

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Submitted on April 7, 2003
Revised on July 2, 2003
Accepted on July 2, 2003

Direct Anti-Inflammatory Mechanisms Contribute to Attenuation of Experimental Allograft Arteriosclerosis by Statins

Koichi Shimizu MD, PhD, Masanori Aikawa MD, PhD, Kiyoshi Takayama PhD, Peter Libby MD, and Richard N. Mitchell MD, PhD^*

From The Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: rmitchell{at}rics.bwh.harvard.edu.

Background--Despite the development of effective immunosuppressive therapy, transplant graft arterial disease (GAD) remains the major limitation to long-term graft survival. The interplay between host inflammatory cells and donor vascular wall cells results in an intimal hyperplastic lesion, which leads to ischemia and graft failure. HMG-CoA reductase inhibitors (statins) reduce GAD in human cardiac allografts, although it is unclear whether this is secondary to cholesterol lowering or other mechanisms. This study tested the hypothesis that statins can suppress GAD by cholesterol-independent pathways.

Methods and Results--We performed heterotopic murine cardiac transplants in total allogeneic or major histocompatibility complex class II-mismatched combinations. Transplanted animals received either control chow, chow containing 25 ppm cerivastatin (low dose), or chow containing 125 ppm cerivastatin (high dose). Mean plasma cerivastatin concentrations were 0.0 (control), 10.1 (low dose), and 21.9 (high dose) nmol/L, respectively. Plasma cholesterol levels were the same in all groups. GAD scores decreased in low-dose (P<0.05) and high-dose (P<0.0001) cerivastatin groups compared with controls, with concomitant reduction in graft-infiltrating cells and significantly decreased intragraft RANTES and monocyte chemotactic protein-1 mRNA expression. Cerivastatin, as well as other statins, also reduced RANTES and monocyte chemotactic protein-1 production in mouse endothelial cells stimulated with interferon- and tumor necrosis factor- in vitro.

Conclusions--Clinically achievable levels of an HMG-CoA reductase inhibitor attenuate GAD in murine heart transplants, diminish host inflammatory cell recruitment, and do not alter cholesterol levels. These results indicate that statins can affect arterial biology and inflammation independently of their effects on cholesterol metabolism.

Key words: statins • inflammation • arteriosclerosis • endothelium • transplantation

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