We show here that (i) eplerenone prevents doxorubicin-induced left ventricular dysfunction in mice, and (ii) this beneficial effect is related to inhibition of MR in cardiac myocytes. Together with present clinical trial data our findings suggest that MR antagonism may be appropriate for the prevention of doxorubicin-induced cardiotoxicity.

Aldosterone is a key factor in adverse cardiovascular remodeling by acting on the mineralocorticoid receptor (MR) in different cell types. Endothelial MR activation mediates hypertrophy, inflammation and fibrosis. Cardiovascular remodeling is often accompanied by impaired angiogenesis, which is a risk factor for the development of heart failure. In this study, we evaluated the impact of MR in endothelial cells on angiogenesis. Deoxycorticosterone acetate (DOCA)-induced hypertension was associated with capillary rarefaction in the heart of WT mice but not of mice with cell type-specific MR deletion in endothelial cells. Consistently, endothelial MR deletion prevented the inhibitory effect of aldosterone on the capillarization of subcutaneously implanted silicon tubes and on capillary sprouting from aortic ring segments. We examined MR-dependent gene expression in cultured endothelial cells by RNA-seq and identified a cluster of differentially regulated genes related to angiogenesis. We found opposing effects on gene expression when comparing activation of the mineralocorticoid receptor in ECs to treatment with vascular endothelial growth factor (VEGF), a potent activator of angiogenesis. In conclusion, we demonstrate here that activation of endothelial cell MR impaired angiogenic capacity and lead to capillary rarefaction in a mouse model of MR-driven hypertension. MR activation opposed VEGF-induced gene expression leading to the dysregulation of angiogenesis-related gene networks in endothelial cells. Our findings underscore the pivotal role of endothelial cell MR in the pathophysiology of hypertension and related heart disease.

Pulmonary hypertension is characterized by progressive remodeling of the pulmonary arteries, however, this is not therapeutically targeted yet. Aldosterone and the MR (mineralocorticoid receptor) are key drivers of cardiovascular disease, and there is a growing body of evidence suggesting a role in pulmonary hypertension. Thus, the aim of this study was to investigate the impact of cell type-specific deletion of MR on pulmonary vascular remodeling. To induce pulmonary hypertension, mice were exposed to chronic hypoxia for 6 weeks. Treatment with the MR antagonist eplerenone attenuated pulmonary vascular remodeling, hypertension, and right ventricular dysfunction. In contrast, aldosterone infusion via osmotic minipumps induced pulmonary vascular remodeling. We created 4 different mouse models with cell type-specific MR deletion in smooth muscle cells, endothelial cells, macrophages, or fibroblasts and exposed them to chronic hypoxia. MR deletion from endothelial cells fully recapitulated the beneficial effects of eplerenone while MR deletion from other cell types had no detectable effect on pulmonary vascular remodeling. RNA-seq from isolated MR-deficient and wildtype pulmonary endothelial cells revealed differentially expressed genes as potential downstream mediators of MR related to pulmonary hypertension, including genes related to the endothelin signaling pathway. MR antagonists improve hypoxia-induced pulmonary vascular remodeling via inhibition of MR in endothelial cells but independent from MR in smooth muscle cells, fibroblasts, or macrophages. The results from this study provide the basis for future investigation of potential downstream mediators of MR involved in pulmonary hypertension and further support the clinical evaluation of MR antagonists in pulmonary hypertension.

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