Abstract 1156: Increased Endothelial Tetrahydrobiopterin Reduces In Stent Stenosis in Apolipoprotein E-Knockout Mice
Excessive intimal hyperplasia, the principal cause of PCI failure, is associated with reduced endothelial nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is a required cofactor for NO synthesis by endothelial nitric oxide synthase (eNOS). We investigated the importance of BH4 in regulating intimal hyperplasia using a transgenic mouse with endothelial overexpression of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase I (GCH). Angioplasty and stenting was performed on aortic segments from donor transgenic mice crossed onto ApoE-KO background (GCH-Tg/ApoE-KO) or their ApoE-KO littermates (n=16), using a novel model of stenting in mice where the stented donor aortic segment is grafted into the carotid artery of isogenic recipients. Aortic BH4 levels were 8-fold higher in GCH-Tg/ApoE-KO mice compared with ApoE-KO controls. (P<0.01). Despite equal stent expansion and injury scores, intimal hyperplasia was reduced by 47% (P<0.001) in GCH-Tg/ApoE-KO mice. Aortic NO synthesis, measured using arginine to citrulline conversion and electron paramagnetic resonance, was not different between groups. However, O2− production was significantly reduced in GCH-Tg/ ApoE-KO mice measured both in aortic sections using oxidative confocal microtopography and in whole aorta by lucigenin enhanced chemiluminescence. NOS inhibition by L-NAME reversed these effects indicating that GCH-Tg/ApoE-KO mice had preserved eNOS coupling. These results indicate that maintaining eNOS coupling and reducing NOS dependent O2− production leads to reduced intimal hyperplasia, and highlight the importance of eNOS regulation in the cellular response to stent injury.