MIF as a target for atherogenesis

Cardiovascular disease has been the most common cause of death in the US each year with the exception of 1918. In 1998, this group of diseases claimed nearly one million lives, which translates to 40% of all deaths (for a detailed analysis of the cardiovascular therapeutics arena access one of our recently featured reports:

• The Cardiovascular Market Outlook to 2008 [more]
• 2003 Cardiovascular Market Update: Part 1 - Anti-hypertensives, Anti-dyslipidemics and Cardiac Therapy [more]

When a coronary artery becomes blocked, blood supply to the myocardium is reduced. Prolonged or severe reduction of blood flow can damage the muscle, resulting in a heart attack. Over 1 million new and recurrent cases of coronary attack occur in the US each year and of these 60% of patients survive. For the survivors and many patients with unstable angina a variety of invasive procedures contribute to the arsenal of therapeutic opportunities available to the clinician. Consequently almost 2 million angioplasty, endarterectomies and bypass procedures are performed each year.

Restenosis caused by vessel injury and accelerated neointima formation is a frequent long-term complication after percutaneous trans-luminal coronary angioplasty in patients with obstructive coronary atherosclerosis. Phenotypically modified smooth muscle cells (SMCs) constitute a major part of restenotic lesions. In addition, macrophages and macrophage-derived foam cells significantly contribute to the neointimal tissue and further aggravate the local inflammatory response and neointimal growth by expression of cytokines and growth factors, especially in the context of hypercholesterolemia. This active inflammation process promotes plaque instability and subsequent thrombosis and preventing the infiltration of monocytes represents an approach to restenosis.

Macrophage migration inhibitory factor (MIF) is a cytokine that stimulates monocyte as well as T-cell recruitment and this cytokine is upregulated in endothelial cells, SMCs, and macrophages during progression of atherosclerotic plaques in humans and in a hypercholesterolemic rabbit model. Interrupting MIF signaling may therefore represent a treatment for restenosis, a hypothesis investigated by Schober et al in their recent Circulation paper.

In this paper the authors report that MIF expression is highly and rapidly increased in the medial SMCs of injured carotid arteries from hypercholesterolemic mice. Expression was greatest close to the site of injury. After 2 weeks expression was predominantly found in macrophages, foam cells and endothelial cells. This over-expression of MIF was pathophysiologically relevant since MIF neutralization reduced the number of macrophages within the neointima, due in part to a reduction in monocyte arrest, and also reduced the percentage of foam cells within the neointimal macrophage population.

This study demonstrates that MIF not only contributes to macrophage accumulation within the neointima but also that it facilitates the development of macrophages into foam cells. The central role that MIF plays in the atherogenic process under conditions mimicking restenosis suggests that therapeutic antibodies targeting MIF (for an analysis of therapeutic antibodies click here) or small molecules able to inhibit MIF signaling may be of considerable use in the prevention of restenosis.

Entry date Wednesday, April 14, 2004

Adapted from Schober et al, Circulation. 2004 Jan 27;109(3):380-5