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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:295.)
© 2006 American Heart Association, Inc.

Vascular Biology

Interleukin-18 and Macrophage Migration Inhibitory Factor Are Associated With Increased Carotid Intima–Media Thickening

Vyacheslav A. Korshunov; Tatiana A. Nikonenko; Vsevolod A. Tkachuk; Andrew Brooks; Bradford C. Berk

From Cardiovascular Research Institute and Department of Medicine (V.A.K., B.C.B.) and Functional Genomics Center (A.B.), University of Rochester, NY; Molecular Endocrinology Laboratory (T.A.N., V.A.T.), Institute of Experimental Cardiology, Russian Cardiology Research and Production Center, Moscow, Russia; and Moscow State University (V.A.T.), Moscow, Russia.

Correspondence to Bradford C. Berk, University of Rochester, Box MED 601 Elmwood Ave, Rochester, NY 14642. E-mail Bradford_Berk{at}URMC.rochester.edu

Objective— Carotid intima–media thickening (IMT) is a form of vascular remodeling that has a strong genetic component. Recently, we discovered that in response to decreased carotid blood flow SJL mice developed the largest intima among 5 inbred strains. Because the SJL strain is prone to autoimmune diseases, we hypothesized that inflammation contributed to IMT in SJL mice.

Methods and Results— We compared vascular remodeling (induced by 2 weeks of low flow) in 2 strains with small IMT (C3H/HeJ and C3HeB/FeJ) versus 2 strains with large IMT (FVB/NJ and SJL/J). Quantitative immunohistochemistry showed a dramatic increase in inflammatory cells per intima area in SJL compared with other strains. Microarray profiling of inflammatory gene mRNAs from carotids showed significant increases in interleukin (IL)-18 and Mif gene expression in SJL compared with C3HeB/FeJ mice. Increased expression of these genes was confirmed by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Furthermore, greater cell proliferation in the intima of SJL accounted for increased intima–media thickening, whereas a higher level of apoptosis and a lower level of proliferation were observed in C3HeB/FeJ mice.

Conclusion— The present study indicates that increased expression of Mif and IL-18 cytokines is associated with intima–media thickening in SJL mice, likely by stimulating inflammation and proliferation.

The role of inflammation was studied in progression of intima–media thickening (IMT) in response to low blood flow in 2 inbred strains of mice. Significantly higher expression of IL-18 and macrophage migratory inhibitor factor proteins was associated with significant differences in IMT between SJL/J and C3HeB/FeJ mice.

Key Words: carotid artery • cytokine • flow • IL-18 • inflammation • intima–media thickening • microarray • Mif • mouse

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