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CARDIOVASCULAR

Selective Clearance of Macrophages in Atherosclerotic Plaques by the Protein Synthesis Inhibitor Cycloheximide

Division of Pharmacology, University of Antwerp, Wilrijk, Belgium (V.C., W.M., A.G.H., G.R.Y.D.M.); and Laboratory of Cell Biology and Histology, University of Antwerp, Wilrijk, Belgium (J.-P.T.)

Macrophages are an essential component of unstable atherosclerotic plaques and play a pivotal role in the destabilization process. We have demonstrated previously that local delivery of the mammalian target of rapamycin (mTOR) inhibitor everolimus selectively clears macrophages in rabbit plaques. Because mTOR controls mRNA translation, inhibition of protein synthesis might induce selective macrophage cell death. We therefore investigated in the present study the effect of the protein synthesis inhibitor cycloheximide on macrophage and smooth muscle cell (SMC) viability. In vitro studies with cultured macrophages and SMCs showed that cycloheximide induced selective apoptosis of macrophages in a concentration- and time-dependent manner. Moreover, macrophages could be selectively depleted in rabbit carotid artery rings with collar-induced atherosclerotic plaques after in vitro treatment with cycloheximide. Local in vivo administration of cycloheximide via osmotic minipumps to rabbit carotid arteries with collar-induced atherosclerotic plaques significantly reduced the macrophage but not the SMC content. Cycloheximide-treated plaques showed signs of apoptosis (increased terminal deoxynucleotidyl transferase end labeling and fluorescein isothiocyanate-Val-Ala-DL-Asp(O-methyl)-fluoromethylketone labeling) that did not colocalize with SMCs. Organ chamber studies demonstrated that the functionality of SMCs and the endothelium were not influenced by cycloheximide treatment. All together, these findings demonstrate that cycloheximide decreases the macrophage load in atherosclerotic plaques by induction of apoptosis without changing SMC content or contractility.

Address correspondence to: Dr. Guido R. Y. De Meyer, Division of Pharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. E-mail: guido.demeyer{at}ua.ac.be

This article has been cited by other articles:

				V. Croons, W. Martinet, A. G. Herman, and G. R. Y. De Meyer Differential Effect of the Protein Synthesis Inhibitors Puromycin and Cycloheximide on Vascular Smooth Muscle Cell Viability J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 824 - 832. [Abstract] [Full Text] [PDF]

				W. Martinet and G. R.Y. De Meyer Selective Depletion of Macrophages in Atherosclerotic Plaques: Myth, Hype, or Reality? Circ. Res., March 30, 2007; 100(6): 751 - 753. [Full Text] [PDF]