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Cardiovasc Res. 2019 May 22. pii: cvz137. doi: 10.1093/cvr/cvz137. [Epub ahead of print]

Aldosterone induces trained immunity: the role of fatty acid synthesis.

Author information

1
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, GA, The Netherlands.
2
Department for Genomics & Immunoregulation, Life and Medical Sciences 12 Institute (LIMES), University of Bonn, Bonn, Germany.

Abstract

AIMS:

Supranormal levels of aldosterone are associated with an increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. In this study, we aimed to investigated whether aldosterone can induce trained immunity in primary human monocytes in vitro and explored the underlying mechanism.

METHODS AND RESULTS:

We exposed human monocytes to aldosterone for 24h, after which they were rested to differentiate into monocyte-derived macrophages for 5 days, and restimulated with Toll-like receptor 2 and 4 ligands on day 6. We demonstrated that aldosterone augments pro-inflammatory cytokine production and reactive oxygen species production in monocyte-derived macrophages after restimulation, via the mineralocorticoid receptor. Fatty acid synthesis was identified as a crucial pathway necessary for this induction of trained immunity and pharmacological inhibition of this pathway blunted aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promoted enrichment of the transcriptionally-permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway.

CONCLUSION:

Aldosterone induces trained immunity in vitro, which is dependent on epigenetically mediated upregulation of fatty acid synthesis. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis and cardiovascular disease.

KEYWORDS:

aldosterone; atherosclerosis; cardiovascular disease; epigenetics; fatty acid synthesis; immunometabolism; macrophage; mineralocorticoid; monocytes

PMID:
31119285
DOI:
10.1093/cvr/cvz137

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