Acriflavine Attenuates the Development of Hypoxic Pulmonary Hypertension

Hypoxia Inducible Factor (HIF) is a highly conserved, heterodimeric transcription factor that has been shown to mediate the development of hypoxia pulmonary hypertension (HPH). Previous studies have identified acriflavine as a drug that binds directly to the PAS-B domain of HIF-1α and HIF-2 α inhibiting dimerization. Therefore, we hypothesized that treatment with acriflavine could reduce the development of HPH. In this study, adult male Wistar rats were weighed daily and injected with 2 mg/kg of acriflavine or saline, while being housed in either room air or in a chamber flushed with a mix of air and nitrogen to achieve 10% O2. After 21 days, we measured right ventricular pressure (RVP) via closed chest cardiac puncture, right ventricle and left ventricle plus septum weights and hematocrit (HCT). Pulmonary arterial smooth muscle cells were isolated from intrapulmonary arteries and used for measurement of intracellular calcium concentration [Ca2+]i using Fura-2 AM. In saline treated animals, chronic hypoxia lead to increased RVP, right ventricle hypertrophy, HCT, and [Ca2+]i. All of these variables were significantly reduced in chronically hypoxic animals receiving acriflavine. These results indicate that acriflavine attenuates the development of HPH.