Abstract 3155: Protective Effect of Endothelial Krüppel-like Transcription Factor- 2 Gene Transfer in the Monocrotaline Model of Pulmonary Hypertension
RATIONALE: Pulmonary Hypertension (PH) is a result of endothelial damage and dysfunction. Krüppel-like factor-2 (KLF2) is a shear-responsive transcription factor thought to maintain endothelial homeostasis. We thus hypothesized that KLF2 expression would be reduced in experimental models of PH, and KLF2 overexpression would have beneficial effects on vascular structure and function.
METHODS: Pulmonary KLF2 mRNA levels were measured in two experimental rat models of PH: chronic hypoxia (CH; 10% O2) which produces moderate, reversible disease; and monocrotaline (MCT; 70mg/kg) which results in severe and fatal PH. KLF2 mRNA expression, right ventricular systolic pressure (RVSP) and RV hypertrophy (RV/LV+Septum) were assessed at 1, 3, 7, or 21 days of CH and 7 or 21 days post MCT. Selective gene transfer of KLF2 or empty plasmid to the pulmonary vasculature was achieved by intravenous injection of jetPEI (Polyplus) with plasmid DNA (150ug) 7 days after MCT injection.
RESULTS: KLF2 mRNA expression was transiently reduced at 3 days of CH (0.3±0.1;p<0.05; normalized to sham), but returned to control levels at 21 days. In contrast, MCT treatment resulted in a sustained reduction in KLF2 expression (0.4±0.09; p<0.05) for 21 days. KLF2 gene transfer 1 week after MCT injury significantly reduced RVSP (41.5±2.9 mmHg vs. 63.7±4.1; p<0.05; n=9 –10) and RV/LV+S weight ratios (0.26±0.01, n=11 vs. 0.35±0.02, n=12 ; p<0.05) compared with sham transfection. RVSP and the RV/LV+S in the group receiving the empty plasmid was no different than MCT alone (n=10).
CONCLUSIONS: These results suggest that KLF2 is protective in experimental PH and that KLF2 may represent a novel therapeutic target for PH.