Circulation, 2012, Vol.126(20), pp.2418-2427
BACKGROUND—: Carotid intima-media thickening is associated with increased cardiovascular risk in humans. We discovered that intima formation and cell proliferation in response to carotid injury is greater in SJL/J (SJL) in comparison with C3HeB/FeJ (C3H/F) mice. The purpose of this study was to identify candidate genes contributing to intima formation. METHODS AND RESULTS—: We performed microarray and bioinformatic analyses of carotid arteries from C3H/F and SJL mice. Kyoto Encyclopedia of Genes and Genomes analysis showed that the ribosome pathway was significantly up-regulated in C3H/F in comparison with SJL mice. Expression of a ribosomal protein, RpL17, was 〉40-fold higher in C3H/F carotids in comparison with SJL. Aortic vascular smooth muscle cells from C3H/F grew slower in comparison to SJL. To determine the role of RpL17 in vascular smooth muscle cell growth regulation, we analyzed the relationship between RpL17 expression and cell cycle progression. Cultured vascular smooth muscle cells from mice, rats, and humans showed that RpL17 expression inversely correlated with growth as shown by decreased cells in S phase and increased cells in G0/G1. To prove that RpL17 acted as a growth inhibitor in vivo, we used pluronic gel delivery of RpL17 small interfering RNA to C3H/F carotid arteries. This resulted in an 8-fold increase in the number of proliferating cells. Furthermore, following partial carotid ligation in SJL mice, RpL17 expression in the intima and media decreased, but the number of proliferating cells increased. CONCLUSIONS—: RpL17 acts as a vascular smooth muscle cell growth inhibitor (akin to a tumor suppressor) and represents a potential therapeutic target to limit carotid intima-media thickening.
Medicine ; Anatomy & Physiology;
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