The role of the mineralocorticoid receptor in immune cells in cardiovascular disease

Abstract

Chronic low-grade inflammation and immune cell activation are important mechanisms in the pathophysiology of cardiovascular disease (CVD). Therefore, targeted immunosuppression is a promising novel therapy to reduce cardiovascular risk. In this review, we identify the mineralocorticoid receptor (MR) on immune cells as a potential target to modulate inflammation. The MR is present in almost all cells of the cardiovascular system, including immune cells. Activation of the MRs in innate and adaptive immune cells induces inflammation which can contribute to CVD, by inducing endothelial dysfunction and hypertension. Moreover, it accelerates atherosclerotic plaque formation and destabilization and impairs tissue regeneration after ischaemic events. Identifying the molecular targets for these non-renal actions of the MR provides promising novel cardiovascular drug targets for mineralocorticoid receptor antagonists (MRAs), which are currently mainly applied in hypertension and heart failure.

Emerging fields for therapeutic targeting of the aldosterone–mineralocorticoid receptor signaling pathway

“…Several experimental studies have demonstrated the pivotal importance of the MR in cells of the innate and adaptive immune system for cardiovascular disease (van der Heijden et al, 2022). Intriguingly, aldosterone by acting on the MR can induce long‐lasting pro‐inflammatory effects in macrophages in the sense of trained immunity.…”

“…Intriguingly, aldosterone by acting on the MR can induce long‐lasting pro‐inflammatory effects in macrophages in the sense of trained immunity. This suggests that the MR might not only play a role in acute inflammatory processes such as myocardial infarction but also chronic low‐grade inflammatory conditions including atherosclerosis or arterial hypertension (van der Heijden et al, 2022).…”

The mineralocorticoid receptor forms higher order oligomers upon DNA binding

“…Thus, MR and GR have distinct but overlapping physiological functions. Inappropriate activation of MR may mimic or counteract GR actions, promoting obesity and metabolic syndrome (14, 15), enhancing inflammation and tissue fibrosis (16) or diminishing it (17) in a tissue-specific fashion (13), or modulating brain responses to stress (18). MR inhibitors, initially used to treat conditions derived from hyperaldosteronism and situations with excessive water retention have increasingly attracted interest as anti-inflammatory and anti-fibrotic targets (19, 20), with important applications to treat cardiovascular disease (21).…”

Deficiency of complement C3a and C5a receptors does not prevent angiotensin II–induced hypertension and hypertensive end-organ damage

“…There is now overwhelming evidence that inflammation and immunity promote the development and maintenance of hypertension. (Drummond et al ., 2019; Hengel et al ., 2021; van der Heijden et al ., 2022; Wenzel et al ., 2016; Wenzel et al ., 2020, Mathis et al ., 2018). However, convincing therapeutic anti-inflammatory approaches to combat hypertension in patients are lacking.…”

“…There is now overwhelming evidence that inflammation and immunity promote the development and maintenance of hypertension. (Drummond et al, 2019;Hengel et al, 2021;van der Heijden et al, 2022;Wenzel et al, 2016;Wenzel et al, 2020, Mathis et al, 2018.…”