Adenoviral GTPCH gene transfer significantly increased maximal acetylcholine-induced vasorelaxation compared to sham treatment in aortic rings from type I (64% vs 37%, P<0.005) and type II diabetic rats.
Does adenoviral GTPCH gene transfer improve NO synthesis and vasorelaxation in endothelial cells and isolated vessels from diabetic rats?
GTPCH gene transfer reverses BH4 deficiency and restores NO production and endothelial function in rat models of type I and type II diabetes, suggesting a potential gene therapy approach for diabetic cardiovascular complications.
Absolute Event Rate: 64% vs 37%
p-value: p=<0.005
Nitric oxide (NO) synthesis in endothelial cells is impaired in diabetes. We previously showed that impaired NO synthesis in the spontaneously diabetic BB (BBd) rat is due to decreased levels of tetrahydrobiopterin (BH4), secondary to decreased expression of GTP cyclohydrolase I (GTPCH). The aim of this study was to utilize adenoviral GTPCH gene transfer to reverse BH4 deficiency and repair the ability of endothelial cells to produce NO. GTPCH gene transfer increased BH4 levels in BBd endothelial cells from 0.17 +/- 0.02 (mean +/-SE) to 73.37 +/- 14.42 pmol/million cells and NO production from 0.77 +/- 0.07 to 18.74 +/- 5.52 nmol/24 h/million cells. To demonstrate a functional effect of increasing BH4 concentrations in tissues, we transferred GTPCH into aortic rings from BBd and Zucker diabetic fatty (ZDF) rats, models of human type I and type II diabetes, respectively. GTPCH gene transfer led to a dose-dependent increase in acetylcholine-induced vasorelaxation, preventable by inhibiting NO synthase. Maximal relaxation of virus-treated rings (10(10) virus particles/ml) to acetylcholine was significantly higher than sham-treated rings (BBd 64% vs. 37%, P<0.005; ZDF 80% vs. 44%, P<0.05). This study demonstrates that GTPCH gene transfer can reverse BH4 deficiency in both type I and type II diabetes and provides an experimental basis for using gene therapy to treat cardiovascular complications in diabetic patients.
Meininger et al. (Tue,) conducted a other in Diabetes (Type I and Type II models). Adenoviral GTP cyclohydrolase I (GTPCH) gene transfer vs. Sham treatment was evaluated on Maximal acetylcholine-induced vasorelaxation in BBd rat aortic rings (p=<0.005). Adenoviral GTPCH gene transfer significantly increased maximal acetylcholine-induced vasorelaxation compared to sham treatment in aortic rings from type I (64% vs 37%, P<0.005) and type II diabetic rats.