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Vascular inflammation and activation: new targets for lipid lowering

M. Aikawa* and P. Libby

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, U.S.A.

* Correspondence: Masanori Aikawa, MD, PhD, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC309, Boston, MA 02115, U.S.A.

Abstract

Inflammatory cells, including macrophages, in atheroma overexpress matrix metalloproteinases (MMPs) and tissue factor which contribute to plaque rupture and thrombosis. Activated smooth muscle cells (SMCs) in the plaque's fibrous cap also express MMPs and tissue factor. Lipid lowering appears to reduce the incidence of acute coronary events in patients by stabilizing atherosclerotic plaques. To improve mechanistic understanding, we tested the hypothesis that experimental manipulation of cholesterol level improves features of atheroma related to their propensity to provoke acute thrombotic complications. In rabbits with established atheroma, dietary lipid lowering reduced accumulation of macrophages expressing MMPs and increased collagen, a key determinant of plaque stability. Lipid lowering also decreased expression of tissue factor and its inducer, CD40 ligand. SMCs in the fibrous cap of rabbit atheroma expressed less MMP and tissue factor after lipid lowering. We have recently found that treatment with an HMG-CoA reductase inhibitor, cerivastatin, retards macrophage accumulation in atheroma of Watanabe heritable hyperlipidaemic (WHHL) rabbits, probably in part by suppressing proliferation. Macrophage expression of MMPs and tissue factor also decreased with cerivastatin treatment in vivo and in vitro. These results support the view that lipid lowering reduces acute thrombotic complications of atherosclerosis in patients by attenuating vascular inflammation.

Key Words: Lipid lowering • atheroma • atherosclerosis

Footnotes

The studies from the Cardiovascular Division of the Brigham and Women's Hospital referred to here were supported by grants from the National Heart, Lung, and Blood Institute (HL-34636, PO1 HL48743) and unrestricted research and educational gifts from Bayer Pharmaceuticals. We acknowledge all our colleagues and collaborators including Elena Rabkin, Seigo Sugiyama, Sami J. Voglic, Masashi Shiomi, Yoshikatsu Okada, Frederick J. Schoen, Mark B. Taubman, John T. Fallon, Eugenia Shvartz, Christopher C. Hill, Yoshihiro Fukumoto, Joseph L. Witztum, Ryozo Nagai, Elissa Simon-Morrissey and Dmitriy Zvagelsky who contributed to the experiments described. We also thank Karen E. Williams for her editorial expertise.


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M. Aikawa, S. Sugiyama, C. C. Hill, S. J. Voglic, E. Rabkin, Y. Fukumoto, F. J. Schoen, J. L. Witztum, and P. Libby
Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma
Circulation, September 10, 2002; 106(11): 1390 - 1396.
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