Abstract 16618: Pharmacological Modulation of PTEN Ameliorates the Progression of Pulmonary Hypertension in Heart Failure
Pulmonary hypertension (PH), that occurs secondary to congestive heart failure, leads to vascular remodeling including neointima formation and vascular occlusion. Currently there is a significant gap in the understanding of the mechanisms involved in vascular remodeling, which, if identified, could provide key therapeutic targets. Phosphatase-and-tensin homolog on chromosome 10 (PTEN) has been implicated in arterial remodeling. However, the involvement of PTEN in PH-mediated vascular remodeling remains unclear. The objective of the present study was to determine the role of PTEN in PH and to develop a therapeutic strategy.
Methods: PH was induced in rats by ligating the left anterior descending (LAD) coronary artery. The onset of PH was monitored by echocardiography and confirmed by hemodynamic measurements. Rats were continuously treated with 100-ppm HO-3867, a promoter of PTEN expression, in the feed for 4 weeks. Control groups did not receive HO-3867. The vascular smooth muscle cells (vSMCs) in the lung were collected using laser capture microdissection. The cells and whole lung tissues were analyzed by western blot, RT-PCR, and qRT-PCR.
Results: The HO-3867 treatment group had a significantly higher ejection fraction (EF) compared to control. Pulmonary arterial and RV systolic pressure data showed the development of PH at 4 weeks post-LAD ligation. Phosphorylated PTEN (Ser380/Thr382/383) was markedly depressed in the PH lungs(43.8% compared to non-PH). Rats treated with HO-3867 showed a significant recovery of PTEN (57.61%). Focal adhesion kinase (FAK) expression was higher in the PH group compared to the HO-3867-treated group. Similar results were obtained at the mRNA levels of the key proteins in the vSMCs collected from lung.
Conclusions: Deregulation of PTEN is involved in PH-mediated vascular remodeling. The vascular remodeling can be inhibited by targeting PTEN pathway using PTEN-promoting agents such as HO-3867.
- © 2011 by American Heart Association, Inc.