Author + information
- Gurdeep Atwal,
- Ying Sun,
- Jiwang Chen and
- Yulia Komarova
Background: Translocation of hypoxia inducible factors (HIFs) from cytoplasm to nucleus of endothelial cells (ECs) plays critical role in pathogenesis of Pulmonary Hypertension (PH). Microtubule (MT) cytoskeleton acts as track for movement of cell organelles and molecules. End Binding protein EB3 at growing MT tips promotes MT growth and interaction with intracellular structures. We test role of EB3 in facilitating PH through stabilization and/or nuclear translocation of HIFs in pulmonary arterial endothelial cells (Fig.1A).
Methods: We developed inducible cell type specific Knock Out (i-KO) mouse models by crossing of EB3fl/fl to Tie2-CreERT2. After 4wks of 10% oxygen hypoxia, PH was measured by echocardiography and jugular vein catheterization. Arterial wall thickness measured by tissue staining and HlF by immunofluorescence.
Results: After hypoxia, both EB3fl/fl (control), iSM-KO (smooth muscle KO) increased Right Systolic Ventricular Pressure (RSVP) but with no significant difference between 2 groups (Fig.1B). RSVP increase was significantly mitigated in EB3 iEC-KO (endothelial cell KO) along with lesser wall (p<0.0001) (Fig 1C) and decreased cytosolic HIF immunofluorescence indicating more degradation (Fig 1D).
Conclusion: MTcytoskeleton is potential target to limit cytosolic movement of HIFs and EB3 can play important cell specific role in limiting hypoxia induced PH. Experiments with EB3 knock down (KD) human pulmonary arterial endothelial cells (HPAECs) are in progress.
Moderated Poster Contributions
Congenital Heart Disease and Pulmonary Hypertension Moderated Poster Theater, Poster Hall, Hall C
Saturday, March 18, 2017, 10:00 a.m.-10:10 a.m.
Session Title: Bridge From the Basics: Translational Research in Pulmonary Hypertension
Abstract Category: 35. Pulmonary Hypertension and Pulmonary Thrombo-embolic Disease
Presentation Number: 1208M-05
- 2017 American College of Cardiology Foundation