Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension

Abstract

Abnormalities that characterize pulmonary arterial hypertension (PAH) include impairment in the structure and function of pulmonary vascular endothelial (EC) and smooth muscle cells (SMC). Aldosterone levels are elevated in human PAH and in experimental pulmonary hypertension (PH), while inhibition of the aldosterone-binding mineralocorticoid receptor (MR) attenuates PH in multiple animal models. We explored the role of MR in ECs and SMCs in using cell specific MR knockout mice exposed to sugen/hypoxia-induced PH. MR inhibition with spironolactone significantly reduced right ventricular (RV) systolic pressure. However, this is not reproduced by selective MR deletion in SMCs or ECs. Similarly, MR inhibition attenuated the increase in RV cardiomyocyte area independent of vascular MR with no effect on RV weight or interstitial fibrosis. RV perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of MR from ECs. EC-MR deletion attenuated the sugen/hypoxia-induced increase in the leukocyte-adhesion molecule, E-selectin, and collagen IIIA1 in the RV. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of EC-MR or SMC-MR. Finally, the degree of pulmonary perivascular inflammation was attenuated by MR antagonism and was fully reproduced by SMC-specific MR deletion. These studies demonstrate that in the sugen/hypoxia PH model, systemic-MR blockade significantly attenuates the disease and that MR has cell-specific effects, with EC-MR contributing to RV perivascular fibrosis and SMC-MR participating in pulmonary vascular inflammation. As MR antagonists are being investigated to treat PAH, these findings support novel mechanisms and potential MR targets that mediate therapeutic benefits in patients.

Mineralocorticoid Receptor Antagonism by Finerenone Attenuates Established Pulmonary Hypertension in Rats

“…The molecular mechanism underlying the protective effects of finerenone against the pulmonary vascular remodeling in the monocrotaline and SuHx rats remains unknown; however, our findings indicate that it may partly be mediated by a decrease in PA-SMC proliferation and a reduction of inflammatory cell infiltration in lungs of finerenone-treated monocrotaline and SuHx rats. These data are consistent with the recent study from Menon and colleagues, 21 which showed that the degree of perivascular lung inflammation is higher in mice with a smooth muscle-specific deletion of MR when they are subjected to SU5416 in combination with chronic hypoxia. Consistent with these results, we also found a significant increase in the percentage of KI67-positive pulmonary vascular cells and a perivascular accumulation of CD68-positive cells in lungs of hMR + mice.…”

“…However, Menon et al 21 recently reported that endothelial MR deletion was not sufficient to protect mice exposed to chronic hypoxia combined with SU5416 injection. However, these 2 different studies found beneficial effects of MR inhibition by eplerenone 12 and spironolactone 21 in these mouse models of experimental PH, respectively. Taken altogether, these studies reveal cell-type specific roles of MR in the context of PAH that are consistent with the decrease in PA-SMC proliferation and the reduction of inflammatory cell infiltration observed in lungs of finerenone-treated monocrotaline and SuHx rats.…”

“…Consistent with this notion, both spironolactone, which is a nonselective steroidal MR antagonist (MRA), and eplerenone, a selective steroidal MRA, have been reported to reduce vascular and cardiac remodeling in monocrotaline and chronic hypoxia models of pulmonary hypertension (PH). 10-14,21…”

“…Consistent with this notion, both spironolactone, which is a nonselective steroidal MR antagonist (MRA), and eplerenone, a selective steroidal MRA, have been reported to reduce vascular and cardiac remodeling in monocrotaline and chronic hypoxia models of pulmonary hypertension (PH). [10][11][12][13][14]21 Finerenone is a first-in-class nonsteroidal MRA that has a higher selectivity and stronger affinity for MR than steroidal MRAs in preclinical models. 22,23 Although chronic treatments with finerenone have anti-inflammatory, anti-fibrotic, and anti-proliferative properties in several in vivo experimental models, [24][25][26][27] its efficacy in rat models of severe PH has not been studied yet.…”

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

“…These findings indicate that the beneficial effects of MRAs on PH may be mainly mediated through the blockade of MR in ECs with indirect effects on PASMCs. It is important to note that this finding could not be reproduced in another study using the hypoxia-sugen model (47). EC-specific MR deletion has been shown to exert benefits on the RV in the hypoxia-sugen mouse model by regulating RV E-selectin and collagen III expression and attenuating RV perivascular fibrosis but did not improve PH (47).…”