Endothelium-targeted transgenic GTP-cyclohydrolase I overexpression inhibits neointima formation in mouse carotid artery.

Journal article

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.

Authors: Liao, S; Lin, L; Zeng, J; Huang, R; Channon, K

• Publication status: Published
• Journal: Clinical and experimental pharmacology and physiology
• Volume: 34
• Issue: 12
• Pages: 1260-1266
• Publication date: 2007-12-01
• DOI: 10.1111/j.1440-1681.2007.04719.x
• EISSN: 1440-1681
• ISSN: 0305-1870
• Language: English
• Keywords: Aorta; Hypertrophy; Coronary Restenosis; Mice, Transgenic; Animals; Mice, Inbred C57BL; Male; Tunica Intima; GTP Cyclohydrolase; Biopterin; Mice; Carotid Arteries; Nitric Oxide