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Review
. 2015 Sep 28:6:153.
doi: 10.3389/fendo.2015.00153. eCollection 2015.

Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis

Affiliations
Review

Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis

Mary E Moss et al. Front Endocrinol (Lausanne). .

Abstract

Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality.

Keywords: aldosterone; atherosclerosis/CAD; mineralocorticoid receptor antagonists; mineralocorticoid receptors; vascular inflammation.

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Figures

Figure 1
Figure 1
Aldo and MR in vascular inflammation. (1) Aldo induces systemic inflammation in the setting of cardiovascular risk factors. (2) In response to endothelial damage, Aldo acts on EC–MR to induce cytokine and adhesion molecule expression. (3) Cytokines produced by the endothelium and underlying SMCs induce EC adhesion molecule expression and leukocyte recruitment, adhesion, and transmigration. (4) Aldo also acts on EC–MR to induce rearrangement of the actin cytoskeleton, possibly facilitating leukocyte transmigration. (5) Myeloid MR induces ROS production and macrophage activation and polarization to the M1 phenotype. (6) MR induces T cell expression of homing markers and differentiation to the Th17 subset. (7) Aldo activation of neutrophil MR induces MMP-9 production, which may promote atherosclerotic plaque rupture.
Figure 2
Figure 2
Mineralocorticoid receptor contributes to vascular inflammation by activation of NFκB. (A) In whole aorta samples, Aldo acting through the MR upregulates the expression of NFκB precursor subunit p105 and downregulates the NFκB inhibitor IκB, promoting transcription of cytokines IL-6, IL-1β, and TNFα. (B) In ECs, inhibition of the MR with eplerenone attenuates expression of NFκB targets ICAM-1, VCAM, and P-selectin (triangles). In rat mesangial cells, regulation of NFκB by the MR was mediated by SGK-1 inhibition of IκB. (C) Aldo exerts both genomic and non-genomic effects on NFκB target genes in SMCs.

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