eplerenone and Hypertension--Pulmonary

[Figure: see text].

Topics: Animals; Antihypertensive Agents; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Eplerenone; Hypertension, Pulmonary; Male; Mice; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Treatment Outcome; Vascular Remodeling

Spironolactone (SPL) improves endothelial dysfunction and survival in heart failure. Immune modulation, including poorly understood mineralocorticoid receptor (MR)-independent effects of SPL might contribute to these benefits and possibly be useful in other inflammatory cardiovascular diseases such as pulmonary arterial hypertension.. Using human embryonic kidney cells (HEK 293) expressing specific nuclear receptors, SPL suppressed NF-κB and AP-1 reporter activity independent of MR and other recognized nuclear receptor partners. NF-κB and AP-1 DNA binding were not affected by SPL and protein synthesis blockade did not interfere with SPL-induced suppression of inflammatory signalling. In contrast, proteasome blockade to inhibit degradation of xeroderma pigmentosum group B complementing protein (XPB), a subunit of the general transcription factor TFIIH, or XPB overexpression both prevented SPL-mediated suppression of inflammation. Similar to HEK 293 cells, a proteasome inhibitor blocked XPB loss and SPL suppression of AP-1 induced target genes in human pulmonary artery endothelial cells (PAECs). Unlike SPL, eplerenone (EPL) did not cause XPB degradation and failed to similarly suppress inflammatory signalling. SPL combined with siRNA XPB knockdown further reduced XPB protein levels and had the greatest effect on PAEC inflammatory gene transcription. Using chromatin-immunoprecipitation, PAEC target gene susceptibility to SPL was associated with low basal RNA polymerase II (RNAPII) occupancy and TNFα-induced RNAPII and XPB recruitment. XP patient-derived fibroblasts carrying an N-terminal but not C-terminal XPB mutations were insensitive to both SPL-mediated XPB degradation and TNFα-induced target gene suppression. Importantly, SPL treatment decreased whole lung XPB protein levels in a monocrotaline rat model of pulmonary hypertension and reduced inflammatory markers in an observational cohort of PAH patients.. SPL has important anti-inflammatory effects independent of aldosterone and MR, not shared with EPL. Drug-induced, proteasome-dependent XPB degradation may be a useful therapeutic approach in cardiovascular diseases driven by inflammation.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; DNA Helicases; DNA-Binding Proteins; Endothelial Cells; Eplerenone; Fibroblasts; HEK293 Cells; Humans; Hypertension, Pulmonary; Inflammation Mediators; Lung; Mineralocorticoid Receptor Antagonists; Mutation; NF-kappa B; Proteasome Endopeptidase Complex; Proteolysis; Pulmonary Artery; Rats, Sprague-Dawley; Retrospective Studies; RNA Polymerase II; Signal Transduction; Spironolactone; Transcription Factor AP-1; Transcription Factor TFIIH

Aldosterone is a mineralocorticoid hormone critically involved in arterial blood pressure regulation. Although pharmacological aldosterone antagonism reduces mortality and morbidity among patients with severe left-sided heart failure, the contribution of aldosterone to the pathobiology of pulmonary arterial hypertension (PAH) and right ventricular (RV) heart failure is not fully understood.. The effects of Eplerenone (0.1% Inspra® mixed in chow) on pulmonary vascular and RV remodeling were evaluated in mice with pulmonary hypertension (PH) caused by Sugen5416 injection with concomitant chronic hypoxia (SuHx) and in a second animal model with established RV dysfunction independent from lung remodeling through surgical pulmonary artery banding.. Preventive Eplerenone administration attenuated the development of PH and pathological remodeling of pulmonary arterioles. Therapeutic aldosterone antagonism - starting when RV dysfunction was established - normalized mineralocorticoid receptor gene expression in the right ventricle without direct effects on either RV structure (Cardiomyocyte hypertrophy, Fibrosis) or function (assessed by non-invasive echocardiography along with intra-cardiac pressure volume measurements), but significantly lowered systemic blood pressure.. Our data indicate that aldosterone antagonism with Eplerenone attenuates pulmonary vascular rather than RV remodeling in PAH.

Topics: Animals; Arterial Pressure; Disease Models, Animal; Eplerenone; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Pulmonary Artery; Ventricular Dysfunction, Right; Ventricular Remodeling