Abstract 13376: PTEN Inactivation by Peroxynitrite Induces Vascular Remodeling in Pulmonary Hypertension Secondary to Left-Heart Failure
Pulmonary hypertension secondary to left-heart failure (LHF-PH; Group 2 PH) originates from LV dysfunction and elevated after-load. The pathogenesis of LHF-PH is characterized by progressive pulmonary vascular remodeling involving smooth muscle cell (SMC) proliferation. However, the mechanism is unknown. We hypothesized that peroxynitrite (PN), a potent oxidant, is a key mediator SMC proliferation. The objective of this study was to determine the involvement and mechanism of PN in vascular SMC proliferation in LHF-PH. LHF was induced by permanent ligation of LAD coronary artery in rats. Echo and hemodynamic measurements were performed to monitor LHF-PH. Histopathology, western-blot (WB), and RT-PCR analyses were also used. Human pulmonary artery SMC (PASMC) was used for in vitro studies. LHF-PH was confirmed by significant elevation of pulmonary artery systolic pressure (57% increase vs control) and vascular remodeling at 4 weeks post-LAD ligation. Nitrotyrosine-staining of lung tissues showed a 6-fold increase of PN generation in LHF rats vs control (Fig A). Activity of PTEN, a dual-function phosphatase known to modulate cell proliferation, was significantly lower (38% vs control) in whole lung and vascular tissues (Fig B). In vitro studies demonstrated low doses of PN (0.5 -1 µM) to induce PASMC proliferation. PTEN cDNA and PTEN siRNA transfection studies clearly implicated PTEN in SMC proliferation. WB analysis showed a dose-dependent inactivation of PTEN by PN. Taken together, the results, for the first time, established the involvement of PN in vascular remodeling via PTEN inactivation. This finding will have important significance in the management of LHF-PH.
- © 2012 by American Heart Association, Inc.