Abstract 17614: 6-mercaptopurine Reduces Progression of Experimentally Induced Pulmonary Arterial Hypertension by Dampening Inflammation and Inhibition of Proliferation
Rationale: Inflammation plays a crucial role in pulmonary arterial hypertension (PAH). Inflammatory cytokines stimulate proliferation of pulmonary arterial smooth muscle cells (PASMC) and endothelial cells (EC). 6-Mercaptopurine (6-MP) is a well-established 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 be a promising treatment of PAH.
Methods: Pulmonary hypertension was induced in male Sprague-Dawley rats by a single injection of SU5416 (25 mg/kg) followed by a 4-week transient exposure to hypoxia and a 2-week normoxic re-exposure. After randomization (treatment vs. vehicle) animals were divided into two groups, receiving 6-MP (1 mg/kg) or vehicle (DMSO) in drinking water from week 1 to 6. Echocardiography was performed at t=0 and t=6. At t=6 rats were anaesthetized for right ventricle (RV) catheterization, after which they were exsanguinated. Both heart and lung tissues were separated for further analysis, including morphometry and immunofluorescence microscopy for markers of inflammation and proliferation.
Results: Compared with vehicle group, 6-MP prevented the elevation of RV systolic pressure, RV afterload and total pulmonary resistance. Accordingly, 6-MP significantly inhibited PA remodeling as revealed by decreased PA wall thickness through reduced intima and media thickness. Moreover, immunofluorescent analysis revealed that 6-MP reduced EC and SMC proliferation and perivascular inflammation. Finally, 6-MP improved cardiac function by improving RV stiffness, stroke volume and cardiac output. In addition, it prevented RV remodeling by reducing wall thickness, end diastolic diameter, myocardial cross sectional area and fibrosis.
Conclusions: 6-MP partly prevented the elevation of RV afterload and PA remodeling by reducing PASMC and PAEC proliferation as well as perivascular inflammation. Together with findings of improved RV remodeling and cardiac function, 6-MP may be a promising intervention of PAH.
Author Disclosures: X. Sun: None. K. Kurakula: None. C. Happé: None. D. da Silva Goncalves Bos: None. I. Schalij: None. H. Bogaard: None. M. Goumans: None.
- © 2016 by American Heart Association, Inc.