Vascular smooth muscle specific anti-proliferative drugs for next-generation drug eluting stents
- 详细技术说明
- Problems Addressed:Impaired re-endothelialization following stent placementIndiscriminate targeting of both EC and VSMC proliferationIntimal hyperplasia
- *Abstract
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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). Using rat balloon injury and mouse wire injury models, the investigators identified CTP synthase 1 (CTPS1) as a target for therapeutics in 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 while having much less effect on EC proliferation. Small molecule 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. The investigators have uncovered a fundamental difference in CTP biosynthesis between SMCs and ECs during vascular remodeling, providing a 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.
- 国家/地区
- 美国
