Blockade of cytidine triphosphate synthase regulates smooth muscle cell and endothelial cell proliferation differentially.

P ercutaneous coronary intervention with stents is currently the most commonly performed coronary revascularization procedure. 1 Two types of coronary stents, bare metal stent and drug-eluting stent (DES), are used. 1 The main complications of stent implantation are in-stent restenosis and stent thrombosis. DES reduced the incidence of restenosis compared with bare metal stent. However, the occurrence of very late stent thrombosis is significantly higher with DES. 2 Clinical and basic studies suggested that DES implantation is associated with retarded re-endothelialization because the drugs eluted from the DESs have inhibitory effects not only on smooth muscle cells (SMCs) but also on endothelial cells (ECs). 3,4 Thus, it would be an ideal strategy to inhibit SMC proliferation without affecting EC survival, proliferation, and migration. Cytidine triphosphate (CTP) is a nucleotide with a pyrimi-dine base. Among all nucleotides, the cellular content of CTP is the lowest, suggesting that the activity of CTP synthesis is tightly regulated. 6 CTP plays an important role in DNA/RNA synthesis, phospholipid synthesis, and protein sialylation, which are required for cell proliferation and cell size expansion. 6 The level of CTP is elevated in various types of cancer cells and, to a lesser extent, in normal proliferating cells. 6 CTP is synthesized from uridine triphosphate by CTP synthase. In mammalian cells, there are 2 isozymes of CTP synthase, that is, CTPS1 and CTPS2. 6 Cyclopentenyl cytosine (CPEC) is an analog of cytidine. CPEC is activated by phosphorylation in cells and metabolized to cyclopentenyl cytosine 5′-triphos-phate (CPEC-TP). CPEC-TP is a noncompetitive inhibitor of CTP synthase and blocks CTP synthesis. CPEC has toxic effects on various kinds of tumor cells. 7 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Tang et al 8 demonstrate that CTP synthase would be an SMC-sensitive therapeutic target for effective vascular repair. Expression of CTPS1 was upregulated in cultured SMCs stimulated by platelet-derived growth factor-BB (PDGF-BB) and in neointima after balloon injury in the rat carotid artery. CTPS1 blockade by CPEC or small hairpin RNA (shRNA) inhibited SMC proliferation in a dose-dependent manner. Low-dose CPEC inhibited SMC proliferation without any effect on ECs. Moreover, CPEC infusion or adenoviral-mediated delivery of CTPS1 shRNA inhibited neointima formation with enhanced re-endothelialization after mechanical injury of the carotid artery in rats and mice. In contrast to CPEC, low-dose paclitaxel, one of the drugs used for DES, inhibited proliferation of both SMCs and ECs. Importantly, ECs were more sensitive …