Aldosterone Regulates Vascular Gene Transcription via Oxidative Stress–Dependent and –Independent Pathways

Newfell, Brenna G.; Iyer, Lakshmanan K.; Mohammad, Najwa N.; McGraw, Adam P.; Ehsan, Afshin; Rosano, Giuseppe; Huang, Paul L.; Mendelsohn, Michael E.; Jaffe, Iris Z.

doi:10.1161/atvbaha.111.229070

Cited by 82 publications

(90 citation statements)

References 44 publications

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“…29,30 We and others, have previously showed that Lcn2/NGAL is a direct target gene of the aldosterone/MR signaling pathway in the cardiovascular system. 5,31,32 The aim of this study was to analyze whether Lcn2/NGAL is a key actor of mineralocorticoid action in the cardiovascular system. We analyzed 2 conditions associated with increased aldosterone/MR activation (AO in human subjects and NAS challenge in a mouse model with Lcn2 gene deletion) and provide mechanistic insights in the profibrotic effects of Lcn2/NGAL.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

et al. 2015

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A ldosterone via the activation of the mineralocorticoid receptor (MR) is a main actor of renal sodium reabsorption and water homeostasis. Extra-renal effects of the mineralocorticoid pathway have now been characterized, especially in the cardiovascular system, opening on new dimensions of the aldosterone/MR pathway in physiology, pathophysiology, and diseases. In the cardiovascular system, mineralocorticoid signaling has been shown to play an important role in the progression of cardiovascular diseases (CVDs). Previous reports using transgenic mouse models or pharmacological approaches demonstrated adverse effects of aldosterone on cardiac remodeling and fibrosis, inflammation, and hypertension.1 These features are prevented by the pharmacological blockade of the MR. In humans, several clinical studies showed the beneficial effects of MR antagonism in addition to standard care, to reduce mortality and morbidity in patients with severe 2 or mild heart failure (HF) 3 or after acute myocardial infarction. 4 Understanding the molecular mechanisms of mineralocorticoid activation pathway in cardiovascular pathophysiology remains incomplete. Indeed, a better knowledge of the underlying mechanisms may highlight novel mediators of the MR signaling cascade. These newly identified intermediates could be good candidates as biotargets for novel pharmacological approaches, especially in diseases where the aldosterone/MR pathway is involved. Moreover, these biotargets may as well be considered as potent biomarkers of MR activation, Abstract-Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs).We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/ mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. allowing a better selectio...

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Section: Discussionmentioning

confidence: 99%

Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

et al. 2015

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“…29 Our results suggest that this increase may be induced (at least partly) by aldosterone. It has been demonstrated that aldosterone regulates CTGF expression ex vivo in various cell types (fibroblasts, 20 smooth muscle cells, 30 and renal mesangial cells) 31 including cardiomyocytes. 32 However, we show here for the first time that CTGF is a direct target of MR, and that aldosterone (but not corticosterone) increases CTGF expression in cardiomyocytes through the stimulation of cardiomyocyte-MR in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Mineralocorticoids can also induce CTGF through other pathways, in the heart, in a serum/glucocorticoid regulated kinase 1-dependent manner 20 and in the vasculature, in an oxidative stress-dependent manner. 30 This does not mean that these pathways are mutually exclusive, and convergent signaling may be involved.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone-Specific Activation of Cardiomyocyte Mineralocorticoid Receptor In Vivo

Messaoudi

Gravez²,

Tarjus³

et al. 2013

Hypertension

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Inappropriate mineralocorticoid receptor (MR) activation is involved in cardiac diseases. Whether and how aldosterone is involved in the deleterious effects of cardiac mineralocorticoid activation is still unclear. Mice overexpressing MR in cardiomyocytes and their controls were treated for 7 days with aldosterone, and cardiac transcriptome was analyzed. Aldosterone regulated 265 genes in cardiomyocyte-targeted MR overexpression mice. Forty three of these genes were also differentially expressed between untreated cardiomyocyte-targeted MR overexpression and controls mice, thus representing putative aldosterone-regulated genes in cardiomyocytes. Among these genes, we focused on connective tissue growth factor (CTGF). In vivo, in cardiomyocyte-targeted MR overexpression mice, aldosterone (but not corticosterone) induced CTGF expression (mRNA and protein) in cardiomyocytes. Ex vivo, aldosterone induced the binding of mineralocorticoid receptor to CTGF promoter and increased the expression of its transcript. Aldosterone induction of CTGF synthesis in cardiomyocytes seems pathologically relevant as the increase in CTGF observed in a model of heart failure (transverse aortic constriction) in rats was prevented by eplerenone, a mineralocorticoid receptor blocker. This study demonstrates that aldosterone specifically regulates gene expression in cardiomyocytes despite large prevalence of glucocorticoids in plasma.

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“…Further candidate MR target genes are proposed through transcriptome analyses on renal, aortic and cardiac tissue after exposure to aldosterone. These have diverse functions in cell signal transduction, oxidative stress, inflammatory mediators, steroid biosynthesis, receptor chaperoning, cellular structure, adhesion and migration (Turchin et al 2006, Latouche et al 2010, Newfell et al 2011, Ueda et al 2014. Comparison between mice with cardiac overexpression of either GR or MR suggests that there is surprisingly little overlap in GR-and MR-regulated genes in the heart (Latouche et al 2010).…”

Section: Expression Of Mr Target Genesmentioning

confidence: 99%

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

Ong

Young

2017

Journal of Molecular Endocrinology

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The mineralocorticoid receptor (MR) and mineralocorticoids regulate epithelial handling of electrolytes, and induces diverse effects on other tissues. Traditionally, the effects of MR were ascribed to ligand-receptor binding and activation of gene transcription. However, the MR also utilises a number of intracellular signalling cascades, often by transactivating unrelated receptors, to change cell function more rapidly. Although aldosterone is the physiological mineralocorticoid, it is not the sole ligand for MR. Tissue-selective and mineralocorticoid-specific effects are conferred through the enzyme 11β-hydroxysteroid dehydrogenase 2, cellular redox status and properties of the MR itself. Furthermore, not all aldosterone effects are mediated via MR, with implication of the involvement of other membrane-bound receptors such as GPER. This review will describe the ligands, receptors and intracellular mechanisms available for mineralocorticoid hormone and receptor signalling and illustrate their complex interactions in physiology and disease.

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Aldosterone Regulates Vascular Gene Transcription via Oxidative Stress–Dependent and –Independent Pathways

Cited by 82 publications

References 44 publications

Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

Aldosterone-Specific Activation of Cardiomyocyte Mineralocorticoid Receptor In Vivo

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

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