| First Author | Liao SJ | Year | 2007 |
| Journal | Clin Exp Pharmacol Physiol | Volume | 34 |
| Issue | 12 | Pages | 1260-6 |
| PubMed ID | 17973864 | Mgi Jnum | J:149049 |
| Mgi Id | MGI:3847418 | Doi | 10.1111/j.1440-1681.2007.04719.x |
| Citation | Liao SJ, et al. (2007) Endothelium-targeted transgenic GTP-cyclohydrolase I overexpression inhibits neointima formation in mouse carotid artery. Clin Exp Pharmacol Physiol 34(12):1260-6 |
| abstractText | 1. Tetrahydrobiopterin (BH(4)) is an essential cofactor that maintains the normal function of endothelial nitric oxide (NO) synthase. Restenosis is a key complication after transluminal angioplasty. Guanosine 5'-triphosphate-cyclohydrolase I (GTPCH) is the first rate-limiting enzyme for de novo BH(4) synthesis. However, the role of GTPCH in restenosis is not fully understood. The present study tested the hypothesis that endothelial-targeted GTPCH overexpression retards neointimal formation, a hallmark of restenosis, in mouse carotid artery. 2. Transluminal wire injury was induced in the left carotid arteries of adult male wild-type C57BL/6 (WT) and endothelial GTPCH transgenic (Tg-GCH) mice. Re-endothelialization was confirmed with in vivo Evans blue staining. Endothelium-dependent and -independent relaxations were measured using isometric tension recording. Morphological analysis was performed 2 and 4 weeks after carotid injury to assess neointimal formation. Fluorescence-based high-performance liquid chromatography (HPLC) was used to determine GTPCH activity and BH(4) levels. Basal NO release following carotid injury was assessed by N(G)-nitro-L-arginine methyl ester-induced vascular contraction. 3. The endothelium was completely removed upon transluminal wire injury and full re-endothelialization was achieved at Day 10. Endothelium-dependent relaxation was impaired 10 days and 4 weeks after carotid injury, whereas endothelium-independent relaxation remained unaffected. Morphological analysis revealed that the endothelial-specific overexpression of GTPCH reduced neointimal formation and medial hypertrophy 2 and 4 weeks after carotid injury. Both arterial GTPCH enzyme activity and BH(4) levels were significantly elevated in Tg-GCH mice compared with WT mice and basal NO release of the injured carotid artery tended to increase in Tg-GCH mice. 4. These findings suggest that the endothelial overexpression of GTPCH increased endothelial BH(4) synthesis and played a preventive role in neointimal formation induced by endothelium denudation. |
