on November 17, 2005
Published online before print November 17, 2005, doi: 10.1161/01.ATV.0000196544.73761.82
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Submitted on June 6, 2005
Accepted on November 3, 2005
Interleukin-18 and Macrophage Migration Inhibitory Factor Are Associated With Increased Carotid Intima-Media Thickening
Vyacheslav A. Korshunov ;
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.
* To whom correspondence should be addressed. 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.
Key words: carotid artery • cytokine • flow • IL-18 • inflammation • intima-media thickening • microarray • Mif • mouse
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