Abstract 15685: Selective Improvement of Pulmonary Arterial Hypertension With Dual ETA/ETB Receptors Antagonist in the Apolipoprotein E-/- Model of PAH and Atherosclerosis
Introduction: Pulmonary arterial hypertension (PAH) is a devastating condition and without treatment is associated with a life expectancy of 2.8 years. Apolipoprotein E deficient (ApoE-/-) mice develop severe PAH and concomitant atherosclerosis when fed a high fat (Paigen) diet (HFD) and have increased levels of endothelin (ET)-1. ET-1 is known to regulate the expression of Interleukin 6 (IL-6) which is also upregulated in PAH and thought to play a significant role in progression of disease. We therefore hypothesised that dual ETA/ETB receptors antagonist macitentan (MACI) would be associated with a reduction in IL-6 and investigated its impact on endothelial function, PAH and atherosclerosis development.
Methods: ApoE-/- mice were fed a HFD from 12 weeks of age for 8 weeks. After 4 weeks of HFD, mice were randomized to either the 4-week treatment group with MACI by food, or were treatment naive (MACI; 30mg/kg/day, CON n=20/group). Echocardiography and closed chest right and left ventricle catheterisation was used to determine PAH phenotype (n=8/group). Prior to sacrifice serum samples were collected for cytokine analysis. Thoracic aortas were collected to assess vascular reactivity using wire myography. Histological analyses of atheroma formation were performed in brachiocephalic and aortic root sections (n=12/group).
Results: MACI reversed PAH as it significantly increased pulmonary artery acceleration time (14.1 vs. 18.3 ms in CON, P<0.05) and reduced right ventricular systolic pressure in HFD-fed ApoE-/-mice compared with treatment naive controls (23 vs. 35 mmHg respectively). MACI treatment was also associated with a significant reduction in IL-6 serum concentration (6.8 vs. 34 pg/ml in CON P<0.01) and an increase in endothelial-dependent relaxation in explanted thoracic aortic rings (P<0.001). There was no significant effect of MACI on atherosclerotic lesion burden, composition or serum levels of TNF-α, IL-1β or IL-10.
Conclusion: Dual blockade of ETA/ETB receptors improves endothelial function and reverses experimental PAH but has no discernible effect on atherosclerosis. The reduction in IL-6, but not other cytokines, further implicates IL-6 in the progression of PAH.
Author Disclosures: N. Arnold: None. L. West: None. A. Braithwaite: None. R. Walker: None. M. Alfaidi: None. L. Renshall: None. J. Chamberlain: None. H. Casbolt: None. C. Holt: None. M. Iglarz: None. S. Francis: None. A. Lawrie: None.
- © 2016 by American Heart Association, Inc.