Mineralocorticoid Receptor Antagonism by Finerenone Attenuates Established Pulmonary Hypertension in Rats

Abstract

Background: We studied the ability of the nonsteroidal MR (mineralocorticoid receptor) antagonist finerenone to attenuate vascular remodeling and pulmonary hypertension using two complementary preclinical models (the monocrotaline and sugen/hypoxia rat models) of severe pulmonary hypertension. Methods: We first examined the distribution pattern of MR in the lungs of patients with pulmonary arterial hypertension (PAH) and in monocrotaline and sugen/hypoxia rat lungs. Subsequent studies were performed to explore the effect of MR inhibition on proliferation of pulmonary artery smooth muscle cells derived from patients with idiopathic PAH. To validate the functional importance of MR activation in the pulmonary vascular remodeling characteristic of pulmonary hypertension, mice overexpressing human MR (hMR+) were studied, and curative treatments with finerenone (1 mg/kg per day by gavage), started 2 weeks after monocrotaline injection or 5 weeks after Sugen injection were realized. Results: We demonstrated that MR is overexpressed in experimental and human PAH and that its inhibition following small interfering RNA-mediated MR silencing or finerenone treatment attenuates proliferation of pulmonary artery smooth muscle cells derived from patients with idiopathic PAH. In addition, we obtained evidence that hMR+ mice display increased right ventricular systolic pressure, right ventricular hypertrophy, and remodeling of pulmonary arterioles. Consistent with these observations, curative treatments with finerenone partially reversed established pulmonary hypertension, reducing total pulmonary vascular resistance and vascular remodeling. Finally, we found that continued finerenone treatment decreases inflammatory cell infiltration and vascular cell proliferation in monocrotaline and sugen/hypoxia rat lungs. Conclusions: Finerenone treatment appears to be a potential therapy for PAH worthy of investigation and evaluation for clinical use in conjunction with current PAH treatments.

Therapeutic targeting of mineralocorticoid receptors in pulmonary hypertension: Insights from basic research

“…Those experimental studies have employed MRAs spironolactone, eplerenone, or finerenone in several models of PH ( Tables 1 , 2 ). The overall finding of those studies is that MRAs can prevent and partially reverse pulmonary vascular remodeling and improve pulmonary hemodynamics in PH ( 43 , 47 , 51 – 53 ) ( Tables 1 , 2 ). Preventive application MRAs attenuated the development of adverse pulmonary vascular remodeling as assesses by attenuated PA muscularization and wall thickening along with decreased PA pressure ( 27 , 44 , 46 , 47 , 51 , 52 , 54 ) ( Table 1 ).…”

“…Beside indirect signaling via MR in PAECs, it has been shown that MR activation in PASMCs is involved in PH progression. A recent study has provided direct experimental evidence that MR is overexpressed in PASMCs of the remodeled PAs in patients with PAH as well as in monocrotaline and hypoxia-sugen rats with established PH ( 43 ). In vitro , aldosterone activates MR in PASMCs in a dose-dependent manner without affecting its expression level ( 44 ).…”

“…In vitro , aldosterone activates MR in PASMCs in a dose-dependent manner without affecting its expression level ( 44 ). The main effect of activated aldosterone-MR signaling in PASMCs is an augmented cell proliferation ( 44 , 45 ), which can be prevented by MRAs ( 44 , 45 ) or MR-directed siRNAs ( 43 ). Aldosterone has been shown to modulate various cellular signaling pathways in PASMCs to promote cell proliferation and survival ( 44 ).…”

“…MR activation in PASMC is also responsible for the perivascular inflammation in PH ( 47 ), likely through the production of a paracrine factor that enhances monocyte chemotaxis ( 48 ). Pharmacological MR blockade exerts protective effects against pulmonary vascular remodeling with decreased PASMC proliferation and reduced inflammatory cell infiltration ( 43 ). Likewise, a lower degree of perivascular lung inflammation in response to hypoxia-sugen was observed in mice with SMC-specific deletion of MR compared to wild type ( 47 ).…”

“…Preventive application MRAs attenuated the development of adverse pulmonary vascular remodeling as assesses by attenuated PA muscularization and wall thickening along with decreased PA pressure ( 27 , 44 , 46 , 47 , 51 , 52 , 54 ) ( Table 1 ). Initiation of MRA therapy after the disease phenotype had established was able to decrease PA muscularization and wall thickening and improve pulmonary hemodynamics ( 26 , 43 , 44 , 46 , 53 ) ( Table 2 ). This applied both to steroidal as well as the novel non-steroidal MRA finerenone ( 43 ).…”