Abstract 15453: HO-3867, a Peroxynitrite Scavenger, Ameliorates Progression of Pulmonary Hypertension Secondary to Left-Heart Failure through Restoration of PTEN activity
Pulmonary hypertension (PH), which develops secondary to left-heart failure (LHF), is a progressive disorder with high mortality and is a contra-indication for heart transplantation. Currently available therapies for PH are limited in scope. Recently, we observed significantly elevated levels of peroxynitrite (PN) in the lungs of rats subjected to LHF. PN induced smooth muscle cell (SMC) proliferation and pulmonary vascular remodeling by inactivating PTEN, a PI3K antagonist known to regulate cell proliferation. The study indicated that PN/PTEN could be used as a potential target for the management of LHF-PH. The goal of this study was to evaluate HO-3867, a dual-function antioxidant/antiproliferative agent, in ameliorating the progression of LHF-PH. In vitro studies established that HO-3867 is a potent scavenger of PN and is antiproliferative against PN-stimulated SMC proliferation (A). PH was induced by permanent ligation of LAD coronary artery in Sprague-Dawley rats for 4 weeks. Echo, hemodynamics, histopathology, and protein analysis were performed. HO-3867 was administered at a dose of 100 ppm in diet for 4 weeks post-ligation. HO-3867 significantly decreased pulmonary artery systolic pressure from 25.4±1.6 to 17.6±1.5 mmHg (p<0.01). H&E staining of HO-3867-treated lungs showed a marked decrease in medial thickening and luminal narrowing (B). Further, HO-3867 attenuated PN by 85%, restored PTEN activity from 53±6% to 84±3% of control (p<0.01), and blunted vascular remodeling without any direct effect on cardiac function. In conclusion, HO-3867 limited the progression of PH secondary to LHF by blunting peroxynitrite stress and restoring PTEN activity.
- © 2012 by American Heart Association, Inc.