Inflammation promotes extra-adrenal-ang II–independent aldosterone release by circulating immune cells in patients with coronary artery disease
A Mroueh, W Fakih, A Trimaille, D S Gong, A Nicolas, A Granier, A Carmona, L Jesel, O Morel, V Schini-KerthAbstract
Background
Aldosterone is a major mediator of cardiovascular remodeling and fibrosis; and is associated with adverse outcomes in heart failure and coronary artery disease (CAD). Traditionally the synthesis of aldosterone is thought to occur exclusively in the adrenal gland cortex by aldosterone synthase (CYP11B2) in response to angiotensin II (Ang II), with limited extra-adrenal production reported in adipose tissue. However, aldosterone signaling has been poorly studied in other tissues and beyond Ang II. Immune cells infiltration in the heart and vasculature is a key event associated with low-grade inflammation and cardiovascular disease, yet the implication of aldosterone signaling in these cells is unclear.
Methods
PBMCs were isolated from 20 healthy donors and 30 patients with stable CAD. Basal CYP11B2 and MR expression were assessed and aldosterone release was quantified. Healthy PBMCs were stimulated with H₂O₂, pro-inflammatory cytokines, Ang II, or aldosterone in the presence or absence of a CYP11B2 inhibitor (FAD286), MR antagonist, AT1R blocker, SGLT2 inhibitor, or aldosterone-neutralizing antibody. Experiments were replicated in CAD PBMCs.
Results
Healthy PBMCs showed low basal CYP11B2/MR expression and minimal aldosterone release (<1 pg/mL). Ang II increased CYP11B2 and MR expression (1.85-fold) and aldosterone release (31.3 ± 6.8 pg/mL). H₂O₂ induced comparable activation (CYP11B2 1.8-fold; aldosterone 29.3 ± 9.3 pg/mL), while pro-inflammatory cytokines elicited the strongest response (CYP11B2 2.35-fold; aldosterone 52.8 ± 8.1 pg/mL) significantly greater than that of Ang II. In contrast, aldosterone reduced CYP11B2 (-18.2%) but increased MR (1.95-fold). In stimulated PBMCs, CYP11B2 inhibition reduced aldosterone to <1 pg/mL and oxidative stress by 48%, whereas MR blockade paradoxically increased aldosterone (77.1 ± 9.6 pg/mL) and reduced oxidative stress by 28%. Aldosterone neutralization and CYP11B2 inhibition were superior to MR blockade in reducing oxidative stress (-43.5% and 47.1% vs 28%). SGLT2 inhibition reduced MR expression (-68.3%) without affecting aldosterone synthesis, while AT1R blockade had minimal effects. CAD PBMCs released higher aldosterone (97.4 ± 12.6 pg/mL), increased CYP11B2 (2.2-fold), MR (1.9-fold) and oxidative stress (2.4-fold). In CAD PBMCs, CYP11B2 inhibition markedly reduced aldosterone (13.2 ± 3.8 pg/mL) and oxidative stress (-46.5%), whereas MR blockade further increased aldosterone (124.9 ± 13.9 pg/mL) with modest oxidative stress reduction (-25.7%).
Conclusion
Aldosterone release by human PBMCs is induced by inflammation and oxidative stress, independently of Ang II, and more pronounced in CAD. Aldosterone inhibition reduces oxidative stress more efficiently than MR blockade. Targeting aldosterone signaling may offer novel approach to reduce circulating cells activation beyond MR inhibition. Notably, SGLT2 inhibition suppresses MR activation, complementing CYP11B2 blockade.