News Release

Old Drugs, New Tricks

Peer-Reviewed Publication

French National Institute for Health and Medical Research (INSERM)

In recent years two Scandinavian studies have shown that fibrates (lipid-lowering drugs) reduce atheroma plaque formation , through an unknown mechanism. Bart Staels and Professor Jean-Charles Fruchart (INSERM 325, Lille 2 University and Lille Pasteur Institute), in collaboration with the teams headed by Jacques Maclouf (INSERM 348, directed by Sylviane Levy-Toledano) and Alain Tedgui (INSERM 141, directed by Bernard Levy), have now discovered why : fibrates have an anti-inflammatory effect on vessel walls.

Fibrates, a class of drugs that reduce blood fat levels, have been used for about a decade in the treatment of some forms of hyperlipidemia and atherosclerosis. Fibrates bind to PPARa, a receptor present in the liver and involved in fatty acid breakdown . PPARa acts as a messenger, allowing the body to adapt to its nutritional environment (especially ingestion of large amounts of fat). Fibrates, synthetic compounds that bind to this receptor, stimulate PPARa activity and thereby reinforce its lipid-lowering action.

The INSERM researchers showed that PPARa receptors are also present in vascular muscle cells, which participate in the formation of atheroma plaque and restenosis after angioplasty . These vascular PPARa receptors were found to inhibit the inflammatory response of the vascular wall which leads to atheroma plaque formation (see inset). Fibrates, by activating PPARa, inhibit the production of inflammatory cytokines such as interleukin-6 (IL-6) and prostaglandin by vascular muscle cells in vitro. They also inhibit the induction of an enzyme called Cox-2 (cyclooxygenase), which serves as a marker of vascular cell inflammation.

The mechanism of action of these PPARa receptors in the vascular wall was also elucidated. The receptors exert at least part of their anti-inflammatory effect by interfering with a signaling pathway called NFkB, which is also activated during inflammatory cytokine production. PPARa inhibits the inflammatory response by inhibiting the NFkB transcription pathway.

This anti-inflammatory action of the fibrates has been confirmed in humans. The researchers compared two groups of 19 patients with mild hyperlipidemia. Only one of the groups had coronary occlusion, and their plasma concentration of IL-6, an inflammatory marker, was twice as high as in the other group. As expected, lipid levels fell in both groups during treatment with a particular type of fibrate. However, the drug also reduced plasma IL-6 levels, to a greater extent in the group with coronary occlusion. Finally, the treatment also caused a fall in the concentration of fibrinogen and CRP (C-reactive protein), two other risk factors for coronary occlusion.

Thus, in addition to their well known lipid-lowering activity, fibrates also have an anti-inflammatory action. This suggests that fibrates may have a beneficial vascular action during the treatment of atherosclerosis and post-angioplasty restenosis, conditions in which activation of vascular muscle cells is a key event. This may justify widening the indications of fibrates to coronary disease not linked to hyperlipidemia.

Atherosclerosis is induced by a large number of factors (hyperlipidemia, hypertension, smoking, some infections, etc.). In response to chronic exposure to these atherogenic factors the vessel wall becomes activated and enters a state of inflammation; recruited macrophages engulf lipids and secrete pro-inflammatory cytokines (mainly interleukin-1 and TNF), leading to cell proliferation and lipid accumulation. Other cytokines (e.g. IL-6 and prostaglandin) are then secreted by muscle cells of the vessel wall, thereby sustaining the inflammatory reaction. The penultimate step in this pathologic process is the entry of some vessel wall cells into a process known as apoptosis (self-destruction); cell debris accumulate and destabilize the atheroma plaque. Myocardial infarction can ensue if the plaque breaks free from the vessel wall.

For further information

"Activation of human aortic smooth muscle cells is inhibited by PPARa but not by PPARg activators."

B. Staels*, W. KoenigY, A. Habib#, R. MervalS, M. Lebret#, I. Pineda Torra*, P. Delerive*, A. Fadel*, G. Chinetti*, J.C. Fruchart*, J. Najib*, J. Maclouf#, A. TedguiS

* U325 INSERM, Institut Pasteur de Lille
# U348 INSERM, hôpital Lariboisière et IFR "Circulation Lariboisière", Paris
S U141 INSERM, Paris
Y University of Ulm, Allemagne

Nature, 25th june 1998, vol 393, pp 790-793

Additional Contact:

Bart Staels
U325 INSERM, Lille
Tél : 33 3 20 87 73 88
e-mail : Bart.Staels@pasteur-lille.fr

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