Conference: 2008 International PHA Conference and Scientific Sessions
Release Date: 06.20.2008
Presentation Type: Abstracts
Swarthout, R.F., Meoli, D.F., Taubman, M.B., Francischetti, I., Awad, H., White, R.J.
Pulmonary & CCM and Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY, USA
Tissue factor (TF) is the membrane glycoprotein that initiates coagulation; it also regulates angiogenesis during development and tumor metastasis. We have observed increased TF expression in PAH patients and in a rat model of severe PAH. We hypothesized that TF contributes to PAH pathogenesis and that blocking TF activity with the tick peptide Ixolaris (IXO) would delay disease progression.
METHODS AND RESULTS: 34 rats underwent left pneumonectomy followed 7 days later by SQ injection of 50 mg/kg monocrotaline (MCT). On day 11 after MCT (d11, RV pressures generally ~60 mmHg), we randomized rats to receive SQ injection of IXO (20 mcg/kg daily) or normal saline (NS) until death. The NS group had 50% mortality by d28; IXO treated animals died an average of 10 days later (p<0.03). In a similar experiment, treatment began at d11 and continued 10 days before rats were acutely vasodilated with sodium nitroprusside and sacrificed for heart weights to measure RV hypertrophy, lung immunohistochemistry to assess TF antigen, and CT scans to visualize vascular pruning. IXO animals had less RV hypertrophy (p<0.01). IXO prevented macrovascular pruning visualized by CT (Figure, represents 3 pairs of rats). Histology showed reduced
neointimal formation in pre-capillary arterioles with IXO treatment, and histochemistry showed reduced TF antigen in IXO treated rats.
CONCLUSION: Inhibition of TF activity delayed disease progression in rats with established PAH, and CT scans confirmed the import of vascular pruning in progressive PAH despite acute vasodilation. TF activity may drive neointimal formation in PAH.