Pathological Role of Serum- and Glucocorticoid-Regulated Kinase 1 in Adverse Ventricular Remodeling

Das, Saumya; Aiba, Takeshi; Rosenberg, Michael; Hessler, Katherine; Xiao, Chunyang; Quintero, Pablo; Ottaviano, Filomena G.; Knight, Ashley; Graham, Evan; Boström, Pontus; Morissette, Michael R.; Monte, Federica del; Begley, Michael J.; Cantley, Lewis C.; Ellinor, Patrick T.; Tomaselli, Gordon F.; Rosenzweig, Anthony

doi:10.1161/circulationaha.112.115592

Cited by 91 publications

(129 citation statements)

References 51 publications

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“…Recently, it has been shown that cardiac SGK1 is activated in human and murine HF and that cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, HF, and induced Na ϩ channel alterations (69). In addition, cardiac SGK1 is activated early after pressure overload induced by transverse aortic, and acute activation promotes cardiomyocyte survival (70).…”

Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

Sabourin

Bartoli

Antigny

et al. 2016

Journal of Biological Chemistry

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Store-operated Ca2؉ entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that up-regulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidence suggests that the mineralocorticoid hormone aldosterone, through activation of its receptor, MR, might be a key regulator of Ca 2؉ influx in cardiomyocytes. We thus assessed whether and how SOCE involving transient receptor potential canonical (TRPC) and Orai1 channels are regulated by aldosterone/MR in neonatal rat ventricular cardiomyocytes. Molecular screening using qRT-PCR and Western blotting demonstrated that aldosterone treatment for 24 h specifically increased the mRNA and/or protein levels of Orai1, TRPC1, -C4, -C5, and stromal interaction molecule 1 through MR activation. These effects were correlated with a specific enhancement of SOCE activities sensitive to store-operated channel inhibitors (SKF-96365 and BTP2) and to a potent Orai1 blocker (S66) and were prevented by TRPC1, -C4, and Orai1 dominant negative mutants or TRPC5 siRNA. A mechanistic approach showed that up-regulation of serum-and glucocorticoid-regulated kinase 1 mRNA expression by aldosterone is involved in enhanced SOCE. Functionally, 24-h aldosterone-enhanced SOCE is associated with increased diastolic [Ca 2؉ ] i , which is blunted by store-operated channel inhibitors. Our study provides the first evidence that aldosterone promotes TRPC1-, -C4-, -C5-, and Orai1-mediated SOCE in cardiomyocytes through an MR and serum-and glucocorticoid-regulated kinase 1 pathway.The last discovered Ca 2ϩ channel family, transient receptor potential canonical (TRPC) 2 and Orai1 channels, is widely expressed, but the role of these channels and the modulation of their expression are not completely understood. Notably, the dysregulation of these important mediators of Ca 2ϩ -dependent signal transduction has been involved in a broad range of human diseases such as adenocarcinomas, type 2 diabetes and diabetic nephropathy, human proteinuric kidney disease focal and segmental glomerulosclerosis, severe immunodeficiency, congenital myopathy, chronic pulmonary disease, and ectodermal dysplasia (1, 2). Although predominantly thought of in the context of non-excitable cells, store-operated Ca 2ϩ entry (SOCE) by store-operated channels (SOCs) has recently emerged as a potential mechanism to alter Ca 2ϩ in the diseased cardiomyocyte. Although still under debate, the prime candidate proteins for SOCs encompass the TRPC channel(s) as non-selective cation channels as well as Orai1, the Ca 2ϩ selective pore-forming unit of the Ca 2ϩ release-activated Ca 2ϩ channel (3). Stromal interaction molecule 1 (STIM1) serves as a Ca 2ϩ sensor in the endoplasmic reticulum/sarcoplasmic reticulum (SR), clustering proximal to the plasma membrane to activate Orai1 (4) and TRPC channel(s) (5) when Ca 2ϩ stores are depleted. The seven isoforms of the T...

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Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

Sabourin

Bartoli

Antigny

et al. 2016

Journal of Biological Chemistry

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“…Various functions of SGK1 have been identified (Salker et al 2011, Borst et al 2012, Das et al 2012, Hall et al 2012. Compelling evidence indicates a role for SGK1 in the development of metabolic syndrome (Lang et al 2009, Lang & Voelkl 2013.…”

Section: Introductionmentioning

confidence: 99%

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

Hao

Pan

et al. 2016

Journal of Molecular Endocrinology

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This study investigates the effectiveness and mechanisms of a serum-and glucocorticoidinducible kinase 1 (SGK1) inhibitor in counteracting hyperglycemia. In an in vivo experiment, we demonstrated that after an 8-week treatment with an SGK1 inhibitor, the fasting blood glucose and HbA1c level significantly decreased in db/db mice. RT-PCR and western blot analyses revealed that intestinal SGK1 and sodium glucose co-transporter 1 (SGLT1) expression were enhanced in db/db mice. Treatment with an SGK1 inhibitor decreased excessive SGLT1 expression in the intestine of db/db mice. In vitro experiments with intestinal IEC-6 cells showed that the co-administration of an SGK1 inhibitor partly reversed the SGLT1 expression and glucose absorption that were induced by dexamethasone. In conclusion, this study revealed that the favorable effect of an SGK1 inhibitor on hyperglycemia is partly due to decreased glucose absorption through SGLT1 in the small intestine. These data collectively suggest that SGK1 may be a potent target for the treatment of diabetes and other metabolic disorders.

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“…Sgk1 is further stimulated by cardiac pressure overload [10,11,12] and genomically upregulated by a variety of further hormones [13] including mineralocorticoids [14,15,16], 1,25-dyhydroxyvitamin D 3 (1,25(OH) 2 D 3 ) [17], gonadotropins [18,19,20,21] and TGFβ [22,23]. The expressed kinase is activated by Phosphoinositide 3-kinase (PI3K) through phosphoinositide-dependent kinase PDK1 [24,25,26,27,28,29,30,31] and by the mammalian target of rapamycin TORC2 protein complex [32].…”

Section: Introductionmentioning

confidence: 99%

“…Altered expression of Sgk1 is associated with cardiac remodeling [10,11,12]. Lack of Sgk1 reduced the cardiac remodeling induced by pressure overload [11,12].…”

Section: Introductionmentioning

confidence: 99%

Sgk1-Dependent Stimulation of Cardiac Na⁺/H⁺Exchanger Nhe1 by Dexamethasone

Voelkl

Pasham

Ahmed

et al. 2013

Cell Physiol Biochem

681

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Background/Aims: The serum- and glucocorticoid-inducible kinase Sgk1 contributes to cardiac remodeling and development of heart failure, which is paralelled by Sgk1-dependent stimulation of the cardiac Na⁺/H⁺ exchanger Nhe1. Glucocorticoids are powerful stimulators of Sgk1 expression and influence cardiac remodeling. The present study thus explored whether the glucocorticoid receptor agonist dexamethasone influenced cardiac Sgk1 expression, as well as activity, expression and phosphorylation at Ser⁷⁰³ of the cardiac Na⁺/H⁺ exchanger Nhe1. Methods: Experiments were performed in HL-1 cardiomyocytes and gene targeted mice lacking functional Sgk1 (sgk1^-/-) and respective wild type mice (sgk1^+/+). Gene expression was determined by quantitative RT-PCR and Nhe1 phosphorylation was determined utilizing a specific antibody against a 14-3-3 binding motif at P-Ser⁷⁰³, which represents a putative phosphorylation site recognition motif for Sgk1 and is involved in Nhe1 activation. Cytosolic pH (pH_i) was determined utilizing 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence and Nhe activity by the Na⁺-dependent realkalinization after an ammonium pulse. Results: Treatment of HL-1 cardiomyocytes with dexamethasone was followed by a significant increase in Sgk1 mRNA expression, parallelled by increased Na⁺/H⁺ exchanger activity. Furthermore, dexamethasone significantly increased Nhe1 and Spp1 mRNA expression. The effects of dexamethasone were blunted by cotreatment of HL-1 cardiomyocytes with the Sgk1 inhibitor EMD638683. Cotreatment with Nhe1 inhibitor cariporide similarly prevented dexamethasone-stimulated Spp1 mRNA expression. In sgk1^+/+ mice, dexamethasone significantly increased cardiac Sgk1 mRNA levels. In sgk1^+/+ mice, but not in sgk1^-/- mice, dexamethasone significantly increased cardiac Nhe1 mRNA expression and Nhe1 phosphorylation at Ser⁷⁰³. Furthermore, cardiac Spp1, Ctgf, Nppa and Nppb mRNA levels were significantly increased in dexamethasone treated sgk1^+/+ mice, effects significantly blunted in sgk1^-/- mice. Conclusions: Sgk1 is critically involved in the phosphorylation and activation of the cardiac Na⁺/H⁺ exchanger Nhe1.

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Pathological Role of Serum- and Glucocorticoid-Regulated Kinase 1 in Adverse Ventricular Remodeling

Cited by 91 publications

References 51 publications

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

Sgk1-Dependent Stimulation of Cardiac Na⁺/H⁺Exchanger Nhe1 by Dexamethasone

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Pathological Role of Serum- and Glucocorticoid-Regulated Kinase 1 in Adverse Ventricular Remodeling

Cited by 91 publications

References 51 publications

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

Sgk1-Dependent Stimulation of Cardiac Na+/H+Exchanger Nhe1 by Dexamethasone

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Sgk1-Dependent Stimulation of Cardiac Na⁺/H⁺Exchanger Nhe1 by Dexamethasone