Print version
Click to downloadSearch Pub Med
Miniribozyme targeted down-regulation of TPH1 in mice protects against chronic hypoxia-induced pulmonary arterial hypertension Tryptophan hydroxylase 1 (TPH1) mediates the generation of 5-HT in the periphery (Walther et al., 2003). Expression of the Tph1 gene is increased in lungs and pulmonary endothelial cells from patients with idiopathic pulmonary arterial hypertension (PAH) (Eddahibi et al., 2006). Hypoxia-induced PAH is ablated in female mice deficient in TPH1 (Tph1-/- mice (Morecroft et al., 2007)). Recently Peter et al (2007) developed a mouse with reduced 5-HT in plasma and whole blood through selective in vivo down-regulation of the Tph1 gene using TPH1-specific miniribozyme technology (tRz186 mice). To investigate if tRz186 mice are protected against hypoxia-induced PAH, we studied the development of PAH after two weeks of hypoxia in tRz186mice and in mice deficient in Tph1 (Tph1-/- mice) for comparison. Male tRz186, Tph1-/- and wild type (WT) mice (FVB/n, 2-3 months, 25-35g) were subjected to 14 days of either hypobaric hypoxia (10% O2) or normoxia. Under isoflurane anaesthesia, mean systemic arterial pressure (mSAP) was obtained via carotid artery cannulation. Right ventricular pressure (sRVP) was obtained by transdiaphragmatic right ventricular cannulation. Systolic right ventricular (RV) / left ventricle+septum (LV+S) ratio was determined as described previously (Morecroft et al., 2007). Statistical comparisons were made by one-way ANOVA with a Tukey’s multiple comparison test. Data are expressed as mean ± s.e.mean. Results are presented in Table 1. Hypoxia induced increases in sRVP and right ventricular hypertrophy in WT mice. Hypoxia-induced increases in sRVP were ablated in tRz and Tph1-/- mice. Under hypoxia, RV/LV+S was elevated in tRz186 and Tph1-/- mice, despite ablation of sRVP. Neither ribozyme-targeted TPH1 disruption or Tph1 knockout had any effect on mean systemic arterial pressure either under chronic hypoxia or normoxia.
Statistical analysis by ANOVA; *P<0.05,***P <0.001 compared with respective normoxic counterparts; n = number of animals |
|||||||||||||||||||||||||||||||||||||||||||