Osmotic regulation of STAT3 stability in H4IIE rat hepatoma cells

AimsThe benefit of the β1-adrenergic receptor (β1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to β-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice.Methods and resultsFollow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ≤25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The β-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the β1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir.ConclusionsIso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via β1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.

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“…17 Hyperosmolar conditions reduce STAT3 expression, 18 which we observed also in NRCM (Supplementary material online, Figure S5 ). …”

Section: Resultssupporting

confidence: 61%

Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy

et al. 2016

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“…Insulin suppressed Stat3-but increased Stat5 mRNA levels. Hyperosmolarity, by itself was essentially without effect (confirming [32] in the case of Stat3) but blunted the insulin response of both genes. In line with an earlier report [17], hyperosmolarity slightly decreased the ATP-dependent bile salt export pump (Bsep, Abcb11) mRNA expression.…”

Section: Table 2amentioning

confidence: 56%

“…This study by DNA array, Northern-and Western blot analysis identified the genes encoding insulin-like growth factor-binding protein (Igfbp1), the multidrug [33], actin (Acta1) [36], tubulin [39], growth hormone receptor (Ghr) [41], multidrug resistance protein (Mrp)2 [16], bile salt export pump (Bsep) [17], the dual specificity phosphatase (Dusp1) [27], signal tranducer and activator of transcription (Stat)3 and γ fibrinogen (Fgg) [32]. The hyperosmotic upregulation of the glycine transporter Glyt (Slc6a9) mRNA reported here (Table 2B, no.…”

Section: Discussionmentioning

confidence: 99%

“…Hepatocyte nuclear factor (Hnf4) α, arginase1 (Arg1) and, in line with [32], γ fibrinogen (Fgg) mRNA expression each were additively downregulated by hyperosmolarity and insulin (Table 2B, no. 58, 82, 75).…”

Section: Osmoregulated Genesmentioning

confidence: 99%

“…Hybridization was carried out in the same solution with approx. 106 cpm/ml [α- 32 P]dCTPlabelled random-primed cDNA probes (Rediprime labelling kit; Amersham Pharmacia Biotech, Little Chalfont, Bucks., U.K). Then, membranes were washed three times in 2xSSC/0.1% SDS for 15min, twice in sodium phosphate buffer (25 mM, pH 7.2)/ EDTA (1mM)/0.1% SDS for 10min and twice in sodium phosphate buffer 10min at 53°C.…”

Section: Northern-blot Analysismentioning

confidence: 99%

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Modulation of Gene Expression Profiles by Hyperosmolarity and Insulin

Schäfer

Gehrmann

Richter

et al. 2007

Cell Physiol Biochem

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Cell hydration changes play a key role in the regulation of cell function and critically affect insulin sensitivity of carbohydrate- and protein metabolism. Here, the modulation of gene expression profiles by hyperosmolarity and insulin was examined in H4IIE rat hepatoma cells by cDNA/oligonucleotiode array-, Northern- and Western blot analysis. Osmosensitive expression of the insulin-like growth factor binding protein Igfbp1, the multidrug resistance protein Mrp5 (Abcc5a) and cyclin D1 (Ccnd1) was established at the mRNA and protein level. Despite a hyperosmotic increase of cyclin D1 mRNA induction by insulin, the cyclin D1 protein expression was decreased by hyperosmolarity, suggesting a hyperosmotic interference with cyclin D1 mRNA translation. Hyperosmolarity at the mRNA level blunted the insulin response of betaine homocysteine-S-methyl transferase, the multidrug resistance proteins Mdr1a (Abcb1a) and 2 (Abcb4), the Igfbp 2 and 5, cyclin G1, dual specificity phosphatase Dusp1, signal transducers and activators of transcription Stat3 and 5, catalase and the bile salt export pump Bsep (Abcb11), whereas the insulin response was increased for Mrp5, cyclin D1 and the phosphoenolpyruvate carboxykinase. Insulin effects on the mRNA expression of the eukaryotic initiation factor 4E binding protein 4e-bp1, tubulin, gene 33, growth hormone receptor, keratin18, ornithine decarboxylase and heme oxygenase 1 were largely insensitive to hyperosmolarity. The data indicate that hyperosmolarity differentially modulates insulin sensitivity at the level of gene expression.

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Evidence that IL‐6‐type cytokine signaling in cardiomyocytes is inhibited by oxidative stress: Parthenolide targets JAK1 activation by generating ROS

Kurdi

Booz

2007

Journal Cellular Physiology

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Parthenolide, an anti-inflammatory compound, was reported to inhibit signal transducer and activator of transcription 3 (STAT3) activation by the interleukin (IL)-6-type cytokines by an undefined process, which was the focus of our study. Here we report that parthenolide reduced both basal and leukemia inhibitory factor (LIF)-induced STAT3 tyrosine 705 (Y705) phosphorylation in cardiomyocytes in a dose-dependent manner, but stimulated the MAP kinase signaling pathways. Activation of Janus kinase 1 (JAK1) tyrosine kinase was markedly reduced by parthenolide. Pretreatment with parthenolide inhibited JAK1-mediated phosphorylation of the LIF receptor subunits LIF receptor (LIFR) alpha and glycoprotein 130 (gp130), and reduced the LIF-induced increase in JAK1 association with both components. In addition, we documented that parthenolide, over the same concentration range, does not have a direct inhibitory effect on JAK1 autophosphorylation. However, we observed that parthenolide increased intracellular reactive oxygen species (ROS). Pretreatment with the antioxidant, N-acetyl-L-cysteine, completely suppressed the effect of parthenolide on JAK1 and STAT3. From these results, we conclude ROS generation in cardiomyocytes blocks STAT3 signaling of the IL-6-type cytokines by targeting JAK1. The finding that signaling by the IL-6-type cytokine may be redox-sensitive defines a novel mechanism of regulation that has implications for exploiting their therapeutic potential.

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Osmotic regulation of STAT3 stability in H4IIE rat hepatoma cells

Cited by 12 publications

References 25 publications

Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy

Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy

Modulation of Gene Expression Profiles by Hyperosmolarity and Insulin

Evidence that IL‐6‐type cytokine signaling in cardiomyocytes is inhibited by oxidative stress: Parthenolide targets JAK1 activation by generating ROS

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