The effect of 6-mercaptopurine treatment on experimentally induced pulmonary arterial hypertension

Background: Inflammation plays a crucial role in the pathogenesis of pulmonary arterial hypertension (PAH), partly by stimulating proliferation of pulmonary arterial smooth muscle cells (SMC) and endothelial cells (EC). 6-Mercaptopurine (6-MP) is an immunosuppressive drug used to treat various autoimmune and chronic inflammatory diseases. Recently, we and others have shown that 6-MP not only inhibits macrophage and T cell activation, but also reduces the proliferation of SMC and EC as well as the inflammatory response of EC. Collectively, given the effects of 6-MP on inflammation, SMC and EC, we hypothesized that 6-MP may become a promising treatment of PAH. Methods: PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 (25 mg/kg) followed by 4-week exposure to hypoxia and 2-week normoxia. At week 6, animals were randomized into vehicle or 6-MP treatment group, by receiving vehicle (DMSO) or 6-MP (7.5 mg/kg/day) in water until week 10. Echocardiography was performed at week 6 and week 10, and right ventricle (RV) catheterization was performed at week 10, after which they were exsanguinated. Both heart and lung tissues were collected for further analysis. Results: Compared to the vehicle group, 6-MP reduced RV systolic pressure, RV afterload and total pulmonary resistance. Moreover, 6-MP improved cardiac function by reducing RV stiffness, and increasing stroke volume and cardiac output. In addition, it partly reversed RV remodeling by reducing RV fibrosis. Conclusion: 6-MP partly reversed RV systolic pressure and RV afterload in established PAH. Together with the observed improved RV remodeling and cardiac function, 6-MP may be a promising intervention for PAH.