Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

Gray, Gillian A.; White, C.; Castellan, Raphael F.P.; McSweeney, Sara J.; Chapman, Karen

doi:10.1530/jme-16-0128

Cited by 33 publications

(33 citation statements)

References 127 publications

(195 reference statements)

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“…Glucocorticoid concentrations are regulated by the hypothalamic-pituitary-adrenal axis, but 11b-HSD1 is the major regulator of the tissue-specific action of glucocorticoids, increasing active glucocorticoid levels within cells and tissues (13). 11b-HSD1 is expressed in cardiomyocytes, vascular smooth muscle cells, fibroblasts, myofibroblasts, and recruited inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

“…Glucocorticoids have been shown to impair infarct healing; however, there are also reports that claim protective effects of glucocorticoids after myocardial ischemia (12)(13)(14)(15)(16). Conflicting results in experimental and clinical studies highlight possibly strict cellspecific and microenvironment-dependent effects of glucocorticoids during wound healing after myocardial infarction.…”

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confidence: 99%

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The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

et al. 2017

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Cell- and tissue-specific actions of glucocorticoids are mediated by the glucocorticoid receptor. Here, we demonstrate that the glucocorticoid receptor (GR) in macrophages is essential for cardiac healing after myocardial infarction. Compared with GRflox (wild-type controls), GRLysMCre mice that lacked GR in myeloid cells showed increased acute mortality as a result of cardiac rupture. Seven days after left coronary artery ligation, GRLysMCre mice exhibited worse cardiac function and adverse remodeling associated with impaired scar formation and angiogenic response to ischemic injury. Inactivation of GR altered the functional differentiation/maturation of monocyte-derived macrophages in the infarcted myocardium. Mechanistically, CD45+/CD11b+/Ly6G−/F4/80+ macrophages isolated from GRLysMCre infarcts showed deregulation of factors that control inflammation, neovascularization, collagen degradation, and scar tissue formation. Moreover, we demonstrate that cardiac fibroblasts sorted from the ischemic myocardium of GRLysMCre mice compared with cells isolated from injured GRflox hearts displayed higher matrix metalloproteinase 2 expression, and we provide evidence that the macrophage GR regulates myofibroblast differentiation in the infarct microenvironment during the early phase of wound healing. In summary, GR signaling in macrophages, playing a crucial role in tissue-repairing mechanisms, could be a potential therapeutic target during wound healing after ischemic myocardial injury.—Galuppo, P., Vettorazzi, S., Hövelmann, J., Scholz, C.-J., Tuckermann, J. P., Bauersachs, J., Fraccarollo, D. The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

et al. 2017

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“…However, understanding the cell‐specific actions of GR activation may suggest more targeted approaches with therapeutic potential. Moreover, recent insights into the pathways involved in tissue‐specific intracellular metabolism of glucocorticoids have suggested novel therapeutic directions (Gray et al, ). The enzyme 11‐β hydroxysteroid dehydrogenase (11‐β‐HSD) catalyses intracellular regeneration of glucocorticoids from inert metabolites.…”

Section: Broad Anti‐inflammatory Interventionsmentioning

confidence: 99%

Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

Huang

Frangogiannis

2018

British J Pharmacology

221

159

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In the infarcted heart, the damage-associated molecular pattern proteins released by necrotic cells trigger both myocardial and systemic inflammatory responses. Induction of chemokines and cytokines and up-regulation of endothelial adhesion molecules mediate leukocyte recruitment in the infarcted myocardium. Inflammatory cells clear the infarct of dead cells and matrix debris and activate repair by myofibroblasts and vascular cells, but may also contribute to adverse fibrotic remodelling of viable segments, accentuate cardiomyocyte apoptosis and exert arrhythmogenic actions. Excessive, prolonged and dysregulated inflammation has been implicated in the pathogenesis of complications and may be involved in the development of heart failure following infarction. Studies in animal models of myocardial infarction (MI) have suggested the effectiveness of pharmacological interventions targeting the inflammatory response. This article provides a brief overview of the cell biology of the post-infarction inflammatory response and discusses the use of pharmacological interventions targeting inflammation following infarction. Therapy with broad anti-inflammatory and immunomodulatory agents may also inhibit important repair pathways, thus exerting detrimental actions in patients with MI. Extensive experimental evidence suggests that targeting specific inflammatory signals, such as the complement cascade, chemokines, cytokines, proteases, selectins and leukocyte integrins, may hold promise. However, clinical translation has proved challenging. Targeting IL-1 may benefit patients with exaggerated post-MI inflammatory responses following infarction, not only by attenuating adverse remodelling but also by stabilizing the atherosclerotic plaque and by inhibiting arrhythmia generation. Identification of the therapeutic window for specific interventions and pathophysiological stratification of MI patients using inflammatory biomarkers and imaging strategies are critical for optimal therapeutic design. Abbreviations11β-HSD, 11-β hydroxysteroid dehydrogenase;

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“…Следует отдельно оговорить, что рост уровня рецепторов происходил на фоне сопоставимой с контролем (5-7-е сутки) и статистически значимо сниженной концентрации плазменного кортикостерона (14-21-е сутки). Однако активные глюкокортикоиды также могут быть регенерированы локально из циркулирующих инертных 11-кето-метаболитов ферментом 11β-гидроксистероиддегидрогеназой 1-го типа [5,11], экспрессия и активность которого в сердце обычно низкие, но могут быстро изменяться в ответ на внешние раздражители [5].…”

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Features of the dynamics of corticosteroid receptors in the myocardium of animals with different resistance to hypoxia in the post resuscitation period

Bayburina

2020

Kazan Med J

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Aim. To characterize the peculiarities of the dynamics of the level of corticosteroid receptors in the myocardium of animals with different resistance to hypoxia in the post-resuscitation period. Methods. Experimental studies were carried out on male non-inbred white rats, divided into 2 groups by hypoxia resistance. A 5-minute arrest of the systemic circulation was modeled under ether anesthesia with intrathoracic clamping of the cardiovascular cluster with subsequent resuscitation. The observation period was 35 days. The content of corticosterone and aldosterone was determined in the blood plasma, the concentration of glucocorticoid and mineralocorticoid receptors in myocard homogenates was determined as well. Results. On days 1 to 3 of the post-resuscitation period in rats highly resistant to hypoxia, the dynamics of plasma corticosterone concentration and the content of corticosteroid receptors was unidirectional. Starting from the 5th day, against the background of a statistically significant decrease in the level of plasma corticosterone, a gradual increase in the density of corticosteroid receptors, mostly glucocorticoid, was observed, most pronounced on the 14th day and remaining until the end of the observation. In animals with low resistance to hypoxia, the dynamics of corticosteroid receptors was characterized by a predominance of mineralocorticoid content in almost all periods of observation. On days 13 of post-resuscitation period on the background of high concentrations of corticosteroid hormones, the minimum content of glucocorticoid receptors was noted. A decrease in the mineralocorticoid receptor level was recorded only on the first day, and in all subsequent periods of the experiment, the control indicators were significantly higher by 1.41.6 times. Strengthened mineralocorticoid signaling in the myocardium, characteristic of animals with low resistance to hypoxia, may be associated with the development of hypertrophy and fibrosis, inflammation, impaired electrical function. An increase in glucocorticoid receptors, characteristic of animals with a high resistance to hypoxia, has an adaptive effect, limiting the inflammatory response, the potential mechanism may be associated with increased expression of type 11-hydroxysteroid dehydrogenase. Conclusion. The identified features can have a significant influence on the course of the post-resuscitation period and determine the long-term forecast.

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Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

Cited by 33 publications

References 127 publications

The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

Features of the dynamics of corticosteroid receptors in the myocardium of animals with different resistance to hypoxia in the post resuscitation period

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