Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis

Moss, M. Elizabeth; Jaffe, Iris Z.

doi:10.3389/fendo.2015.00153

Cited by 33 publications

(28 citation statements)

References 55 publications

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“…Perhaps more importantly, the ALDO-induced increase in plaque lipid and inflammatory cell content was also prevented in mice lacking ICAM-1. This has important clinical implications since a plaque phenotype with increased lipids and inflammatory cells is known to contribute to susceptibility to rupture, the cause of most MIs and strokes [16]. This mechanism may therefore explain the increased risk of MI and stroke in patients with elevated ALDO levels [2,4].…”

Section: Discussionmentioning

confidence: 99%

“…Intravascular leukocytes then take up lipids and form the core of the atherosclerotic plaque. Plaques with increased inflammatory cell infiltrate and lipid content are prone to rupture and thrombosis, and this vulnerable plaque phenotype is the cause of most MIs and strokes [16]. Thus, understanding mechanisms driving plaque progression and inflammation and the role of ALDO/MR, may explain the clinical observations linking ALDO to cardiovascular ischemia.…”

Section: Introductionmentioning

confidence: 99%

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Essential role of ICAM-1 in aldosterone-induced atherosclerosis

Marzolla

Armani

Mammi

et al. 2017

International Journal of Cardiology

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Objective Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression. Methods and Results Apolipoprotein-E (ApoE)−/− mice fed an atherogenic diet and treated with aldosterone for 4 weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE−/−/ICAM-1−/−) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1. Conclusions Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Essential role of ICAM-1 in aldosterone-induced atherosclerosis

Marzolla

Armani

Mammi

et al. 2017

International Journal of Cardiology

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“…Animal studies have shown that these antagonists inhibit atherosclerosis, whereas aldosterone, an endogenous agonist of MR, promotes atherosclerosis (8,12). Utilizing a myeloid MR knock-out (MRKO) mouse model, we and others have previously demonstrated that MR regulates macrophage polarization and inflammation and that macrophage MR is important in controlling cardiac and vascular remodeling (13)(14)(15)(16)(17).…”

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confidence: 99%

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Atherosclerosis by Affecting Foam Cell Formation and Efferocytosis

Shen

Chen

Sun

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerMineralocorticoid receptor (MR) has been considered as a potential target for treating atherosclerosis. However, the cellular and molecular mechanisms are not completely understood. We aim to explore the functions and mechanisms of macrophage MR in atherosclerosis. Atherosclerosis-susceptible LDLRKO chimeric mice with bone marrow cells from floxed control mice or from myeloid MR knock-out (MRKO) mice were generated and fed with high cholesterol diet. Oil red O staining showed that MRKO decreased atherosclerotic lesion area in LDLRKO mice. In another mouse model of atherosclerosis, MRKO/APOEKO mice and floxed control/APOEKO mice were generated and treated with angiotensin II. Similarly, MRKO inhibited the atherosclerotic lesion area in APOEKO mice. Histological analysis showed that MRKO increased collagen coverage and decreased necrosis and macrophage accumulation in the lesions. In vitro results demonstrated that MRKO suppressed macrophage foam cell formation and up-regulated the expression of genes involved in cholesterol efflux. Furthermore, MRKO decreased accumulation of apoptotic cells and increased effective efferocytosis in atherosclerotic lesions. In vitro study further revealed that MRKO increased the phagocytic index of macrophages without affecting their apoptosis. In conclusion, MRKO reduces high cholesterol-or angiotensin II-induced atherosclerosis and favorably changes plaque composition, likely improving plaque stability. Mechanistically, MR deficiency suppresses macrophage foam cell formation and up-regulates expression of genes related to cholesterol efflux, as well as increases effective efferocytosis and phagocytic capacity of macrophages.Atherosclerosis is the underlying basis of coronary heart disease and cerebrovascular disease, which together account for nearly 80% of all deaths caused by cardiovascular diseases (1). Atherosclerotic cardiovascular diseases remain to be a leading cause of mortality and morbidity worldwide, posing a great threat to public health (2). New strategies and new targets are in need to treat atherosclerosis more effectively.Macrophages are the major immune cells in atherosclerotic plaques and play essential roles during the whole process of atherosclerosis in different aspects, including inflammation, foam cell formation, necrosis, and phagocytic clearance (3, 4). In the early stages, macrophages accumulated in the subendothelial space ingest modified lipids to become foam cells that are a hallmark of atherosclerosis and the major component of early fatty streak lesions (5). These macrophage-derived foam cells secrete inflammatory cytokines and chemokines to amplify inflammatory response and to induce more accumulation of macrophages/foam cells, propelling expansion and progression of atherosclerotic plaques. In advanced lesions, apoptosis of macrophages/foam cells rapidly increases, whereas the ability of neighboring macrophages/foam cells to effectively clear the apoptotic cells (effective efferocytosis) decreases, both of which contribu...

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“…MR is a hormone-activated transcription factor and most of its long term effects, including renal regulation of blood pressure, are mediated by its genomic actions to regulate gene transcription. Chronic MR antagonism modulates expression of genes that can offset or reverse the initial impairment in endothelium-dependent dilation including activation of anti-oxidant and anti-inflammatory pathways in the endothelium (Reviewed in (Moss and Jaffe 2015)).…”

Section: Discussionmentioning

confidence: 99%

Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults

Hwang

Yoo

Luttrell

et al. 2016

Experimental Gerontology

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Mineralocorticoid receptor (MR) activation by aldosterone may regulate vascular function in health or contribute to vascular dysfunction in cardiovascular disease. Whether the effects are beneficial or detrimental to vascular function appear to be dependent on the integrity of the vascular endothelium and whether the responses are short-term or chronic. Acute modulation of MR activation has resulted in conflicting outcomes on vascular function in young healthy adults. Little is known about the vascular role of aldosterone and MR activation in healthy human aging. The primary objective of this study was to examine whether acute inhibition of MR by the selective antagonist eplerenone, influences vascular function in healthy older adults. We performed a randomized, double-blind, placebo-controlled crossover study in 22 adults (61±1 y; mean ± SE, 53–79 y) who were free from overt clinical cardiovascular disease. We measured brachial artery flow-mediated endothelium-dependent dilation and endothelium-independent dilation to sublingual nitroglycerin (0.4mg) following eplerenone (100 mg/dose, 2 doses, 24 hours between doses) or placebo. In response to acute MR antagonism, flow-mediated dilation decreased by 19% (from 6.9±0.5 to 5.6±0.6 %, P=0.02; placebo vs. eplerenone). Endothelial nitric oxide synthase (eNOS) activity also decreased following MR antagonism based on the ratio of phosphorylated eNOSSer1177 to total eNOS (1.53±0.08 vs. 1.29±0.06, P=0.02). Nitroglycerin-induced dilation and blood pressure were unaffected (nitroglycerin-induced dilation: 21.9±1.9 vs. 21.0±1.5 %, P=0.5 and systolic/diastolic blood pressure: 135/77±4/2 vs. 134/77± 4/2 mmHg, P ≥0.6). In conclusion, acute MR antagonism impairs vascular endothelial function in healthy older adults without influencing vascular smooth muscle responsiveness to exogenous nitric oxide or blood pressure.

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Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis

Cited by 33 publications

References 55 publications

Essential role of ICAM-1 in aldosterone-induced atherosclerosis

Essential role of ICAM-1 in aldosterone-induced atherosclerosis

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Atherosclerosis by Affecting Foam Cell Formation and Efferocytosis

Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults

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