title: Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension.
abstract: Mineralocorticoid receptor (MR) activation stimulates systemic vascular and left ventricular remodeling. We hypothesized that MR contributes to pulmonary vascular and right ventricular (RV) remodeling of pulmonary hypertension (PH). We evaluated the efficacy of MR antagonism by spironolactone in two experimental PH models; mouse chronic hypoxia-induced PH (prevention model) and rat monocrotaline-induced PH (prevention and treatment models). Last, the biological function of the MR was analyzed in cultured distal pulmonary artery smooth muscle cells (PASMCs). In hypoxic PH mice, spironolactone attenuated the increase in RV systolic pressure, pulmonary arterial muscularization, and RV fibrosis. In rat monocrotaline-induced PH (prevention arm), spironolactone attenuated pulmonary vascular resistance and pulmonary vascular remodeling. In the established disease (treatment arm), spironolactone decreased RV systolic pressure and pulmonary vascular resistance with no significant effect on histological measures of pulmonary vascular remodeling, or RV fibrosis. Spironolactone decreased RV cardiomyocyte size modestly with no significant effect on RV mass, systemic blood pressure, cardiac output, or body weight, suggesting a predominantly local pulmonary vascular effect. In distal PASMCs, MR was expressed and localized diffusely. Treatment with the MR agonist aldosterone, hypoxia, or platelet-derived growth factor promoted MR translocation to the nucleus, activated MR transcriptional function, and stimulated PASMC proliferation, while spironolactone blocked these effects. In summary, MR is active in distal PASMCs, and its antagonism prevents PASMC proliferation and attenuates experimental PH. These data suggest that MR is involved in the pathogenesis of PH via effects on PASMCs and that MR antagonism may represent a novel therapeutic target for this disease.
authors: Tupper Research Institute and Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Boston, MA 02111, USA. ipreston@tuftsmedicalcenter.org
authors: Ioana R
authors: IR
authors: Preston
authors: Kristen D
authors: KD
authors: Sagliani
authors: Rod R
authors: RR
authors: Warburton
authors: Nicholas S
authors: NS
authors: Hill
authors: Barry L
authors: BL
authors: Fanburg
authors: Iris Z
authors: IZ
authors: Jaffe
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D010982:Platelet-Derived Growth Factor; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone
keywords: aldosterone; hypoxia; monocrotaline; pulmonary vascular remodeling; spironolactone