Published Online
on June 14, 2004

A more recent version of this article appeared on June 29, 2004

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Submitted on February 5, 2004
Revised on April 23, 2004
Accepted on May 20, 2004

Macrophage Migration Inhibitory Factor Deficiency Impairs Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Jie-Hong Pan MD, PhD, Galina K. Sukhova PhD, Jing-Tian Yang PhD, Bing Wang MD, PhD, Tao Xie BS, Huanxiang Fu MD, Yaou Zhang MD, PhD, Abhay R. Satoskar MD, PhD, John R. David MD, Christine N. Metz PhD, Richard Bucala MD, PhD, Kenneth Fang MD, Daniel I. Simon MD, Harold A. Chapman MD, Peter Libby MD, and Guo-Ping Shi DSc^*

From the Department of Medicine (J-H.P., B.W., T.X., Y.Z., K.F., H.A.C., G-P.S.), University of California San Francisco, Calif; Department of Medicine (G.K.S., D.I.S., P.L.), Brigham and Women’s Hospital/Harvard Medical School, Boston, Mass; Department of Chemistry (J-T.Y.) and Medicine (H.F.), Huzhou Teacher’s College, China; Department of Immunology and Infectious Disease (A.R.S., J.R.D.), Harvard School of Public Health, Boston, Mass; The North Shore-Long Island Jewish Research Institute (C.N.M.), NY; and Yale University School of Medicine (R.B.), New Haven, Conn.

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

Background--Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine expressed widely by vascular cells. However, scant in vivo evidence supports direct participation of MIF in atherogenesis. Therefore, we investigated whether deficiency of MIF modulates atherosclerotic lesion formation and composition in low-density lipoprotein receptor-deficient (LDLr^-/-) mice.

Methods and Results--MIF^-/-LDLr^-/- and LDLr^-/- mice were generated and consumed an atherogenic diet for 12 or 26 weeks. MIF^-/-LDLr^-/- mice had significantly reduced abdominal aorta lipid deposition and intimal thickening from aortic arch throughout the abdominal aorta compared with LDLr^-/- mice. Marked retardation of atherosclerosis over time in MIF-deficient mice accompanied decreased lesion cell proliferation. At 26 weeks, 20% of MIF-deficient mice developed only early, fatty streak-like lesions, whereas >80% of LDLr^-/- mice developed advanced lesions containing calcification and lipid cores. Analysis of smooth muscle cells from mouse aortae demonstrated that MIF deficiency reduced smooth muscle cell proliferation, cysteine protease expression, and elastinolytic and collagenolytic activities.

Conclusions--Deficiency of MIF reduces atherogenesis in LDLr^-/- mice. These results provide novel insight into inflammatory pathways operating in atheromata and identify a new potential target for modulating atherogenesis.

Key words: atherosclerosis • cathepsins • smooth muscle cells

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