title: CTP synthase 1, a smooth muscle-sensitive therapeutic target for effective vascular repair.
abstract: OBJECTIVE
  Vascular remodeling as a result of smooth muscle cell (SMC) proliferation and neointima formation is a major medical challenge in cardiovascular intervention. However, antineointima drugs often indistinguishably block re-endothelialization, an essential step toward successful vascular repair, because of their nonspecific effect on endothelial cells (ECs). The objective of this study is to identify a therapeutic target that differentially regulates SMC and EC proliferation.
  
  
  RESULTS
  Using both rat balloon injury and mouse wire injury models, we identified CTP synthase 1 (CTPS1) as one of the potential targets that may be used for developing therapeutics for treating neointima-related disorders. CTPS1 was induced in proliferative SMCs in vitro and neointima SMCs in vivo. Blockade of CTPS1 expression by small hairpin RNA or activity by cyclopentenyl cytosine suppressed SMC proliferation and neointima formation. Surprisingly, cyclopentenyl cytosine had much less effect on EC proliferation. Of importance, blockade of CTPS1 in vivo sustained the re-endothelialization as a result of induction of CTP synthesis salvage pathway enzymes nucleoside-diphosphate kinase A and B in ECs. Diphosphate kinase B seemed to preserve EC proliferation via use of extracellular cytidine to synthesize CTP. Indeed, blockade of both CTPS1 and diphosphate kinase B suppressed EC proliferation in vitro and the re-endothelialization in vivo.
  
  
  CONCLUSIONS
  Our study uncovered a fundamental difference in CTP biosynthesis between SMCs and ECs during vascular remodeling, which provided a novel strategy by using cyclopentenyl cytosine or other CTPS1 inhibitors to selectively block SMC proliferation without disturbing or even promoting re-endothelialization for effective vascular repair after injury.
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens, GA (R.T., X.-B.C., J.-N.W., S.-Y.C.); and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.).
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Cui
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Wang
authors.forename: Shi-You
authors.initials: SY
authors.lastname: Chen
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism; D058426:Neointima; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D057772:Vascular System Injuries / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*
chemical_list: D004791:Enzyme Inhibitors; D054778:NM23 Nucleoside Diphosphate Kinases; D003562:Cytidine; C045911:cyclopentenyl cytosine; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase
keywords: CTP synthase 1; nucleoside diphosphate kinase; reendothelialization; smooth muscle proliferation; vascular remodeling