Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

Griol-Charhbili, Violaine; Fassot, Céline; Messaoudi, Smail; Perret, C.; Agrapart, Vincent; Jaisser, Frédéric

doi:10.1161/hypertensionaha.110.153619

Cited by 35 publications

(36 citation statements)

References 42 publications

(50 reference statements)

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Section: Tarjus Et Al Ngal Mediates Mineralocorticoids Fibrotic Effecsupporting

confidence: 82%

“…22 Gene inactivation of Lcn2 did not affect vascular response to these agents ( Figure 2A; Table S2) as previously reported. 23 Therefore, NAS treatment modified the contractile phenotype regardless the Lcn2 genotype because Lcn2 inactivation had no effect on NAS-induced alterations in vascular response.…”

Section: Lcn2 Gene Inactivation Limits the Vascular Fibrosis Induced supporting

confidence: 82%

“…NAS challenge in WT mice decreased the aortic vasodilatory response to acetylcholine (endothelium-dependent vasorelaxation; Figure 2A; Table S2) and sodium nitroprusside (endothelium-independent vasorelaxation; Figure 2B; Table S2) and increased the vasoconstrictive response to phenylephrine (a vasoconstrictor α-adrenergic agonist) as previously reported ( Figure 2C; Table S2). 22 Gene inactivation of Lcn2 did not affect vascular response to these agents ( Figure 2A; Table S2) as previously reported.23 Therefore, NAS treatment modified the contractile phenotype regardless the Lcn2 genotype because Lcn2 inactivation had no effect on NAS-induced alterations in vascular response. NAS-induced increased protein carbonylation related to oxidative stress and osteopontin expression in aorta of WT mice but not of Lcn2 knockout mice ( Figure 3A and 3B).…”

supporting

confidence: 78%

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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: Tarjus Et Al Ngal Mediates Mineralocorticoids Fibrotic Effecsupporting

confidence: 82%

Section: Lcn2 Gene Inactivation Limits the Vascular Fibrosis Induced supporting

confidence: 82%

supporting

confidence: 78%

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

et al. 2015

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“…It has been suggested that the vascular pathological effects of aldosterone/MR result from inflammation, increased vascular reactive oxygen species, and decreased nitric oxide production (4,22,23). Such mechanisms are observed in animal models when mineralocorticoid pathway activation is associated with nephrectomy and salt excess, ischemia, or pressure overload (24,25). In the absence of associated pathology, enhanced mineralocorticoid activation per se may lead to distinct pathological events through other mechanisms that are not fully elucidated, such as ion channel remodeling (25).…”

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

Zhao

Célérier²,

Bousquet³

et al. 2012

J. Clin. Invest.

335

296

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Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. In CSCR, dilation and leakage of choroid vessels underneath the retina cause subretinal fluid accumulation and retinal detachment. Because glucocorticoids induce and aggravate CSCR and are known to bind to the mineralocorticoid receptor (MR), CSCR may be related to inappropriate MR activation. Our aim was to assess the effect of MR activation on rat choroidal vasculature and translate the results to CSCR patients. Intravitreous injection of the glucocorticoid corticosterone in rat eyes induced choroidal enlargement. Aldosterone, a specific MR activator, elicited the same effect, producing choroid vessel dilation -and leakage. We identified an underlying mechanism of this effect: aldosterone upregulated the endothelial vasodilatory K channel KCa2.3. Its blockade prevented aldosterone-induced thickening. To translate these findings, we treated 2 patients with chronic nonresolved CSCR with oral eplerenone, a specific MR antagonist, for 5 weeks, and observed impressive and rapid resolution of retinal detachment and choroidal vasodilation as well as improved visual acuity. The benefit was maintained 5 months after eplerenone withdrawal. Our results identify MR signaling as a pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, which suggests that blockade of MR could be used therapeutically to reverse choroid vasculopathy.

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“…7 Several lines of available evidence clearly demonstrate an important role also for endothelial cells in the response to aldosterone. 8 In this issue of the journal, Griol-Charhbili et al 9 describe their studies using an established mutant mouse to explore the role of the epidermal growth factor receptor (EGFR) in the vascular response to MR activation.…”

mentioning

confidence: 99%

Mineralocorticoid and Epidermal Growth Factor Receptors

Rickard¹,

Fuller²

2011

Hypertension

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See related article, pp 238 -244I n the decade since the publication of the Randomized Aldactone Evaluation Study (RALES), 1 interest in the role of aldosterone and the mineralocorticoid receptor (MR) has increased exponentially. The comfortable notion that mineralocorticoid hypertension was just a matter of salt and water has been supplanted by a recognition that multiple tissues and systems are impacted. 2,3 It is clear that the adverse cardiovascular consequences of mineralocorticoid-induced hypertension are far in excess of what might be expected for the magnitude and duration of the blood pressure rise. 4 These observations have focused research on the consequences of MR activation in nonepithelial tissues. 5 This represents somewhat of a renaissance as the consequences for the cardiovascular system of exposure to mineralocorticoids was first noted by Hans Seyle in 1946 and rediscovered by Brilla and Weber with further characterization by Young et al. 6 These investigators established a robust rodent model of mineralocorticoid-induced hypertension, cardiac hypertrophy, and cardiac fibrosis resulting from mineralocorticoid/salt administration over a period of weeks. The cardiac fibrosis is preceded by vascular inflammation and is independent of the hypertension, cardiac hypertrophy, angiotensin II, and potassium status. It is blocked by coadministration of MR antagonists (spironolactone or eplerenone) and, more importantly, once established, as in RALES, can be reversed by MR blockade. 6 The response involves a number of tissues and/or cell types, including vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts, and inflammatory cells, particularly those of the monocyte/macrophage lineage. The identification of the relative contribution of each of these cell types, all of which, with the exception of the fibroblasts, contain the MR, is a critical first step in understanding the response. In Hypertension last year, tissue-specific deletion of MR was used to demonstrate a critical role for macrophage MR in the pathological response, although curiously this was without effect on the mononuclear cell infiltration per se. 7

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Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

Cited by 35 publications

References 42 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

Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

Mineralocorticoid and Epidermal Growth Factor Receptors

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