Abstract 1325: Selective Kinase Inhibition Attenuates Rodent Pulmonary Arterial Hypertension (PAH)
Introduction: PAH exhibits significant overlap with cancer pathophysiology with aberrancies in signal transduction and abnormal cellular proliferation (endothelium, smooth muscle). This results in an angioproliferative vasculopathy.
Goal: We assessed the safety and efficacy of sorafenib as a potential therapy for PAH. Sorafenib, currently approved for cancer treatment, inhibits critical kinases involved in angiogenesis (Raf-1 kinase inhibitor, VEGFR-2, VEGFR-3, PDGFR-β).
Hypothesis: Sorafenib prevents PAH in a rodent model.
Methods: We performed two 3-week studies in a rodent PAH model (hypoxia + VEGFR2 blockade with SU5416) using Dahl Salt Sensitive (SS) rats. Two groups of animals (15 rats followed by 18 rats) were divided into 5 groups: normoxia + vehicle, hypoxia + vehicle, hypoxia + SU5416, hypoxia + sorafenib, and hypoxia + sorafenib + SU5416. Except for the normoxia group, all rats were maintained in a hypoxia chamber with a fraction inspired oxygen content (FiO2) of 10%. Rats were given 1 injection of SU5416 at day 1 (20 mg/kg). Sorafenib solution was administered daily by gavage (2.5mg/kg). Echocardiograms were performed at day 1 and at day 22. Hemodynamics were preformed at day 22.
Results: Hypoxia/ SU5416 rats developed severe arterial remodeling, whereas hypoxic rats had mildly elevated pressures compared with normoxia. In contrast, there was no significant change in pressures or weights in the hypoxia plus sorafenib group and a >40% reduction in the hypoxia +sorafenib + SU5416 group. This was confirmed by histopathology.
Conclusion: Sorafenib provides a beneficial effect on pulmonary remodeling and PAH in rodents, and may be a safe and potential therapeutic agent for the treatment of human PAH.