Title: Abstract 17982: Krìppel-Like Transcription Factor- 2 Preserves Endothelial Function and Protects Against Pulmonary Hypertension
Abstract: RATIONALE: Pulmonary Hypertension (PH) is associated with ongoing endothelial cell (EC) dysfunction. Shear-responsive Krüppel-like Transcription Factor- 2 (KLF2) is thought to maintain EC homeostasis and to enhance NO bioavailability by inducing eNOS transcription and decreasing caveolin-1 expression. Thus, we hypothesized that KLF2 expression would be reduced in experimental PH, and KLF2 overexpression would prevent pulmonary arterial (PA) remodeling and preserve EC function in chronic hypoxia (CH)-induced PH. METHODS: Lung KLF2 mRNA levels were measured at 1, 3, 7, or 21 days in the CH (10% O2) rat model of PH. Selective gene transfer of KLF2 or empty plasmid to lung ECs was achieved by intravenous injection of jetPEI™ with plasmid DNA (150µg) at day 3 of CH. At 21 days of CH, right ventricular systolic pressure (RVSP), RV hypertrophy, and medial area in PAs with external diameters of <30µm and 30-50µm were assessed. Ex vivo lung functional analyses were performed and eNOS expression was assessed 24 hrs after shKLF2 delivery. RESULTS: KLF2 mRNA expression was reduced at 3 days of CH (0.3±0.1;P<0.05; normalized to sham), returning to control levels at 7 and 21 days. Compared with control transfection, KLF2 gene therapy reduced RVSP (69.5 ± 6.5 vs. 46.5 ± 2.6 mmHg; P<0.01; n=11-13) and RV/LV+S weight ratios (0.35 ± 0.02 vs. 0.28 ± 0.01, n=11-13; P<0.05), associated with a 1.3 fold increase in lung eNOS expression (P=0.04), but no change in PA medial area at day 21. Moreover, KLF2 knockdown resulted in increased RVSP in normoxic rats, matched with reduced eNOS expression to 0.60 ± 0.08 fold and a blunted vasodilator response to ACh (-4.68 ± 0.99 vs. -7.17 ± 0.80 ⋔mmHg; P<0.01; n=6), while SNP-induced dilation was unchanged (n=4) compared to transfected controls (RS). CONCLUSIONS: These results suggest that KLF2 is protective in the CH model of PH. The mechanism of protection involved maintenance of eNOS expression and endothelial dilatory function, rather than vascular remodeling.
Publication Year: 2011
Publication Date: 2011-11-22
Language: en
Type: article
Indexed In: ['crossref']
Access and Citation
Cited By Count: 4
AI Researcher Chatbot
Get quick answers to your questions about the article from our AI researcher chatbot