The Effects of Spironolactone on Inflammation in a Rodent Model of Pulmonary Arterial Hypertension

Clinical Center

Investigators

Linked publications & trials

Abstract

PAH encompasses a group of rare but lethal diseases characterized by progressive narrowing and occlusion of the small pulmonary arteries, stress on the right-side of the heart and eventually death from right-heart failure. New treatments are urgently needed because current therapy does not reverse this progressive disease and 50% of patients die within 7 years of their diagnosis. Inflammation has recently been recognized as an important part of the abnormal pulmonary arteries in patients with PAH, and therefore it has been hypothesized that drugs that block inflammation may have benefits in patients with PAH. Mineralocorticoid receptor (MR) antagonists improve patient outcomes in variety of cardiovascular diseases. Treatment with spironolactone or eplerenone, both MR antagonists, improves right heart function and pulmonary artery pressure in animal models of pulmonary hypertension. These effects are primarily believed to be a result of inhibiting the harmful effects of MR. While mineralocorticoid receptor (MR) independent anti-inflammatory effects of spironolactone have been recognized for decades, the mechanism was not understood. However, MR-independent mechanisms and the effects of spironolactone on inflammation in PAH have not been previously studied. Our group has uncovered an MR-independent mechanism whereby spironolactone suppresses inflammation in pulmonary artery endothelial cells in vitro. We identified XPB degradation as a shared, MR-independent mechanism by which spironolactone inhibits both NF-B and AP-1 inflammatory signaling. Unlike spironolactone, eplerenone did not cause XPB degradation and failed to suppress inflammatory signaling (Elinoff JM et al. Cardiovasc Res. 2018). Parts 1 and 2 of the study have been completed. A manuscript describing the effects of MR antagonists on cardiac index and ventricular interdependence in the SU-5416/hypoxia/normoxia rat model of PAH is currently in preparation. The following was accepted for presentation at the American Heart Association Scientific Session, 2019: Lu M, Mazer AJ, Anderson SA, Gairhe S, Chen LY, Nelson JNH, Noguchi A, Yu ZX, Wang H, Sun J, Danner RL, Solomon MA, Elinoff JM. Mineralocorticoid Receptor Antagonists Prevent Further Decline in Cardiac Index and Improve Ventricular Interdependence in a Rat Model of Pulmonary Arterial Hypertension.