Modulation of transcriptional mineralocorticoid receptor activity by nitrosative stress

Ruhs, Stefanie; Strätz, Nicole; Schlör, K. H.; Meinel, Sandra; Mildenberger, Sigrid; Rabe, Sindy; Gekle, Michael; Großmann, Claudia

doi:10.1016/j.freeradbiomed.2012.06.028

Cited by 17 publications

(17 citation statements)

References 54 publications

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“…The authors noted that while these and other pro-fibrotic genes are upregulated in the MR overexpressing mice, the phenotype remains mild until the addition of Ang II. The requirement for a second 'hit' is consistent with other studies [21, 23, 39–42] and our recent finding of aldosterone-worsened cardiac rupture in mice after MI [9]. The identification of these MR selective targets indicates that aldosterone/MR recruits multiple pathways to regulate the extracellular matrix and that phenotypic outcome is context dependent.…”

Section: Aldosterone-stimulated Signaling Pathwayssupporting

confidence: 88%

Aldosterone and cardiovascular disease: the heart of the matter

Anderson

2013

Trends in Endocrinology & Metabolism

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Aldosterone contributes to the endocrine basis of heart failure and studies on cardiac aldosterone signaling have reinforced its value as a therapeutic target. Recent focus has shifted to new roles of aldosterone that appear to depend on co-existing pathologic stimuli, cell type, and disease etiology. This review evaluates recent advances in mechanisms underlying aldosterone-induced cardiac disease and highlights the interplay between aldosterone and Ca2+ and calmodulin dependent protein kinase II, whose hyperactivity during heart failure contributes to disease progression. Increasing evidence implicates aldosterone in diastolic dysfunction, and there is need to develop more targeted therapeutics such as aldosterone synthase inhibitors and molecularly specific anti-oxidants. Despite accumulating knowledge, many questions still persist and will likely dictate areas of future research.

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Section: Aldosterone-stimulated Signaling Pathwayssupporting

confidence: 88%

Aldosterone and cardiovascular disease: the heart of the matter

Anderson

2013

Trends in Endocrinology & Metabolism

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“…While aldosterone is implicated as the activator of the MR responsible for tissue inflammation in human clinical situations, including in the heart where 11β-HSD2 expression is limited (61), it has been difficult to explain how the MR is activated because circulating aldosterone concentrations are most often normal or low. Increased ROS from any source has been found experimentally to activate MR independently of ligand (118, 128, 175, 388). An alternative proposal is that in many nonepithelial tissues, for example, the heart, occupation of MR by glucocorticoids limits MR function; oxidative stress changes the conformation and activates the quiescent MR:cort complexes (135, 258).…”

Section: Pathophysiological Implications Of Inappropriate Mr Activationmentioning

confidence: 98%

“…Under normal conditions NO suppresses transcriptional MR activity, suggesting that NO treatment mitigates excessive and pathophysiological effects. In contrast, peroxynitrite formed by the reaction of NO with excessive ROS was found to induce ligand independent MR nuclear translocation and transactivation without activating GR (388). An alternative proposal is that in many nonepithelial cells the MR is bound to glucocorticoid in a quiescent conformation that is rendered active under conditions of severe oxidative stress such as that of heart failure, resulting in inappropriate MR activation (135).…”

Section: Mammalian Adrenocorticosteroids and Their Receptorsmentioning

confidence: 99%

The Multifaceted Mineralocorticoid Receptor

Gómez-Sánchez

2014

Comprehensive Physiology

247

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The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect.

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“…Besides the ligand-dependent activation, there are also modulators of the MR that act ligand-independently. Treatment with peroxynitrite (ONOO À ) in the absence of ligand induced MR transactivation activity whereas genomic GR activity was not affected [106]. Nagase et al demonstrated that oxidative stress causes MR activation in rat cultured cardiomyocytes and thereby may also contribute to pathophysiological effects.…”

Section: Micromilieu Modulatorsmentioning

confidence: 99%