scholarly journals Cardiac Ablation of SOCS3 Aggravates DOCA-Salt-Induced Hypertrophic Remodeling by Activation of Gp130-Dependent Signaling in Mice

2018 ◽  
Vol 47 (1) ◽  
pp. 140-150 ◽  
Author(s):  
Shuang Liu ◽  
Li-Xin Liu ◽  
Yun-Long Zhang ◽  
Song Lai ◽  
Yun-Peng Xie ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Hypertensive Heart Disease ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Potential Therapeutic Target ◽  
Protein Levels ◽  
Gp130 Receptor

Background/Aims: Cardiac remodeling is a critical pathogenetic process leading to heart failure. Suppressor of cytokine signaling-3 (SOCS3) is demonstrated as a key negative regulator of the gp130 receptor to inhibit cardiac hypertrophy. However, the role of SOCS3 in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. Methods: Cardiac-specific SOCS3 knockout (SOCS3cKO) and wild-type (WT) C57BL/6J mice were subjected to uninephrectomy and DOCA-salt for 3 weeks. The effect of SOCS3 on cardiac remodeling and inflammation was evaluated by histological analysis. Gene and protein levels were measured by real-time PCR and immunoblotting analysis. Results: After DOCA-salt treatment, the expression of SOCS3, activation of gp130/JAK/STAT3, cardiac dysfunction and fibrosis in DOCA-salt mice were significantly elevated, which were markedly attenuated by eplerenone, a specific mineralocorticoid receptor (MR) blocker. Moreover, DOCA-salt-induced cardiac dysfunction, hypertrophy, fibrosis and inflammation were aggravated in SOCS3cKO mice, but were significantly reduced in AAV9-SOCS3-injected mice. These effects were mostly associated with activation of gp130/STAT3/AKT/ERK1/2, TGF-β/Smad2/3 and NF-κB signaling pathways. Conclusions: Our data demonstrate that loss of SOCS3 in cardiomyocytes promotes DOCA-salt-induced cardiac remodeling and inflammation, and it may be a novel potential therapeutic target for hypertensive heart disease.

scholarly journals The role of suppressor of cytokine signaling 1 as a negative regulator for aberrant expansion of CD8α+ dendritic cell subset

2005 ◽  
Vol 17 (9) ◽  
pp. 1167-1178 ◽  
Author(s):  
Jun Tsukada ◽  
Akemi Ozaki ◽  
Toshikatsu Hanada ◽  
Takatoshi Chinen ◽  
Ryo Abe ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Cell Subset ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Dendritic Cell Subset ◽  
Suppressor Of Cytokine Signaling

Abstract 021: Role of Central Nervous System Suppressor of Cytokine Signaling 3 (socs3) in Regulating Metabolic and Cardiovascular Function in Obesity

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Jussara M do Carmo ◽  
John N Freeman ◽  
Alexandre A da Silva ◽  
Sydney P Moak ◽  
John E Hall
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glucose Tolerance ◽  
Cardiovascular Effects ◽  
Negative Regulator ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Female Mice

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of leptin signaling, is upregulated in obesity and may contribute to development of leptin resistance. We determined whether deletion of SOCS3 in the entire central nervous system (CNS) would protect mice from adverse metabolic and cardiovascular effects of a high fat diet (HFD). SOCS3 flox/flox /Nestin-cre mice were generated by breeding SOCS3 flox/flox with Nestin-Cre mice. Male and female mice with CNS deletion of SOCS3 (SOCS3 flox/flox /Nestin-Cre, n=5-10) or control (SOCS3 flox/flox , n=6-10) were fed a HFD plus sucrose from 6 until 22 weeks of age. Mean arterial pressure (MAP) and heart rate (HR) were recorded by telemetry and oxygen consumption (VO 2 ) was monitored by indirect calorimetry in 22-week-old mice. Compared to control mice, SOCS3 flox/flox /Nestin-Cre mice were lighter (male: 34±3 vs. 45±3 and female: 27±1 vs. 37±2 g) and had elevated VO 2 (94±12 vs. 69±6 ml/kg/min) but there were no significant differences in food intake (male: 3.3±0.7 vs. 3.8±0.5 and female: 3.0±0.6 vs. 3.0±0.5 g/day) or plasma glucose (male: 148±8 vs. 198±31 and female 149±12 vs. 164±12 mg/dl). Male SOCS3 flox/flox /Nestin-Cre mice had similar MAP (115±2 vs. 116±1 mmHg) but higher HR (657±3 vs. 592±3 bpm) compared to control mice. However, female SOCS3 flox/flox /Nestin-cre mice had higher MAP (121±1 vs. 108±1 mmHg) and HR (655±2 vs. 606±5 bpm) compared to control mice. No significant differences were observed in glucose tolerance in SOCS3 flox/flox /Nestin-Cre vs. control mice (AUC: 391±36 vs. 429±54 mg/dL x 120 min in males and 459±70 vs. 372±51 mg/dL x 120 min in females). These results indicate that CNS SOCS3 deletion reduced body weight and increased energy expenditure and HR but did not improve glucose tolerance in male or female mice fed a HFD. However, HFD significantly increased BP in female SOCS3 flox/flox /Nestin-Cre mice compared to control mice fed a HFD, suggesting a sex difference in the role of CNS SOCS3 signaling in BP regulation in obesity. (NHLBI PO1HL51971and NIGMS P20GM104357)

Abstract P235: Balancing Truss Expression Paves a Way for Cardiac Hypertrophy Therapy

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hongliang Li ◽  
Xiao-Jing Zhang ◽  
Ke-Qiong Deng
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Negative Regulator ◽  
Scaffolding Protein ◽  
Dependent Manner ◽  
Ang Ii ◽  
Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy, which is always accompanied by cardiac fibrosis and the resultant cardiac dysfunction, leads to hear failure and even sudden death. The TNF-receptor ubiquitous signaling and scaffolding protein (TRUSS) that is enriched in the heart has been identified as a negative regulator of cancer. However, the role of TRUSS in cardiac remodeling is unknown. Here, we aimed to investigate the potential participation of TRUSS in cardiac hypertrophy and the molecular events by which TRUSS regulates this pathological condition. The pathological cardiac hypertrophy model was established by pressure overload in vivo and Ang II stimulation in vitro . We observed that the expression level of TRUSS was dramatically increased in the heart and in primary cardiomyocytes upon pro-hypertrophic stimuli. To illustrate the functional role of TRUSS in cardiac remodeling, the cardiac specific knockout (KO) or transgenic (TG) mice were employed. After aortic binding (AB) for 4 weeks, TRUSS deficiency conferred significant resistance to pressure overload via significantly inhibiting cardiomyocytes enlargement and fibrosis formation by about 37% and 46%, respectively, whereas dramatically exacerbated hypertrophy, fibrosis, and cardiac dysfunction were shown in TRUSS-TG mice compared to their littermate controls. Mechanistically, TRUSS can directly bind to JNK, a well-known pro-hypertrophic factor, and activate its downstream pathway. Further investigations indicated that the aggravated effect of TRUSS on cardiac hypertrophy can be almost completely reversed by a specific JNK inhibitor, SP600125, indicating a JNK-dependent manner of TRUSS-regulated cardiac hypertrophy. The directly exacerbated function of TRUSS in cardiomyocytes and the JNK-dependent mechanisms were further validated in primary cardiomyocytes that treated with Ang II after infection with AdshTRUSS or AdTRUSS. Notably, the increased protein and mRNA expression of TRUSS was also observed in heart samples from patients with hypertrophic cardiac myopathy. In conclusion, TRUSS functions as a positive regulator of pathological cardiac hypertrophy, suggesting a promising therapeutic approach for the hypertrophy related heart diseases by balancing TRUSS expression.

scholarly journals Absence of suppressor of cytokine signaling 2 turns cardiomyocytes unresponsive to LIF-dependent increases in Ca2+ levels

2017 ◽  
Vol 312 (4) ◽  
pp. C478-C486 ◽  
Author(s):  
Cibele Rocha-Resende ◽  
Itamar Couto Guedes de Jesus ◽  
Danilo Roman-Campos ◽  
Artur S. Miranda ◽  
Fabiana Alves ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Cytokine Signaling ◽  
Wild Type ◽  
Suppressor Of Cytokine Signaling ◽  
Gp130 Receptor ◽  
Intracellular Ca ◽  
Full Activation

Little is known regarding the role of suppressor of cytokine signaling (SOCS) in the control of cytokine signaling in cardiomyocytes. We investigated the consequences of SOCS2 ablation for leukemia inhibitory factor (LIF)-induced enhancement of intracellular Ca2+ ([Ca2+]i) transient by performing experiments with cardiomyocytes from SOCS2-knockout (ko) mice. Similar levels of SOCS3 transcripts were seen in cardiomyocytes from wild-type and SOCS2-ko mice, while SOCS1 mRNA was reduced in SOCS2-ko. Immunoprecipitation experiments showed increased SOCS3 association with gp130 receptor in SOCS2-ko myocytes. Measurements of Ca2+ in wild-type myocytes exposed to LIF showed a significant increase in the magnitude of the Ca2+ transient. This change was absent in LIF-treated SOCS2-ko cells. LIF activation of ERK and STAT3 was observed in both wild-type and SOCS2-ko cells, indicating that in SOCS2-ko, LIF receptors were functional, despite the lack of effect in the Ca2+ transient. In wild-type cells, LIF-induced increase in [Ca2+]i and phospholamban Thr17 [PLN(Thr17)] phosphorylation was inhibited by KN-93, indicating a role for CaMKII in LIF-induced Ca2+ raise. LIF-induced phosphorylation of PLN(Thr17) was abrogated in SOCS2-ko myocytes. In wild-type cardiomyocytes, LIF treatment increased L-type Ca2+ current ( ICa,L), a key activator of CaMKII in response to LIF. Conversely, SOCS2-ko myocytes failed to activate ICa,L in response to LIF, providing a rationale for the lack of LIF effect on Ca2+ transient. Our data show that absence of SOCS2 turns cardiomyocytes unresponsive to LIF-induced [Ca2+] raise, indicating that endogenous levels of SOCS2 are crucial for full activation of LIF signaling in the heart.

Abstract P076: Suppressor of Cytokine Signaling 3 (SOCS3) in POMC Neurons and Its Role in Regulating Blood Pressure, Body Weight and Glucose in Obesity

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Zhen Wang ◽  
Jussara M do Carmo ◽  
Alexandre A da Silva ◽  
John E Hall
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Food Intake ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Male And Female ◽  
Female Mice ◽  
And Control

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of leptin signaling, may be involved in development of obesity-induced leptin resistance. Although we previously showed that activation of proopiomelanocortin (POMC) neurons mediates the chronic effects of leptin on blood pressure (BP), the role of SOCS3 in modulating BP in obesity is still unclear. In this study, we investigated the role of SOCS3 specifically in POMC neurons in regulating body weight, glucose handling and BP in mice fed a normal or high fat (45%, HFD) chow. Male and female SOCS3flox/flox-POMC/cre mice in which SOCS3 was selectively deleted in POMC neurons and control SOCS3flox/flox mice were used. Food intake and body weight were measured from 8 to 16 weeks of age, and a glucose tolerance test (GTT) was performed at 20 wks of age. At 22 wks of age, mice were implanted with telemetry probe to measure BP and heart rate (HR) and fed a HFD for 6 weeks. Compared to control mice, both male and female SOCS3flox/flox-POMC/cre mice were lighter at 16 wks (29.1 ± 3.5 vs 31.9 ± 3.6 g in male and 21.5 ± 2.2 vs 26.1 ± 5.7 in female, n=9-11, p<0.05) but food intake was similar in both groups. Only male SOCS3flox/flox-POMC/cre mice exhibited improved glucose handling (AUC: 1059 ± 52 vs 1283 ± 54 mg/dL x 120 min, n=7-10, p<0.05 ) and no differences were observed in female mice. When fed normal chow, BP was similar in SOCS3flox/flox-POMC/cre and control mice (116 ± 7 vs 113 ± 5 mmHg) at 23 wks. After a HFD for 6 weeks, SOCS3flox/flox-POMC/cre mice had a greater BP increase compared to control mice (7.2 ± 1.9 vs 0.9 ± 1.8 mmHg, n=4-9, P<0.05) but no significant differences were observed in food intake or body weight between two groups. These results suggest that SOCS3 deletion specifically in POMC neurons reduced body weight in male and female mice, and improved glucose handling only in male mice. HFD increased BP in SOCS3flox/flox-POMC/cre but not in control mice, suggesting that SOCS3 in POMC neurons may modulate BP response to HFD.

scholarly journals The role of CXC-chemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma

BMC Cancer ◽  
2014 ◽  
Vol 14 (1) ◽  
Author(s):  
Anastasios Stofas ◽  
Georgia Levidou ◽  
Christina Piperi ◽  
Christos Adamopoulos ◽  
Georgia Dalagiorgou ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Chemokine Receptor ◽  
Renal Cell ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Cxc Chemokine ◽  
Chemokine Receptor Cxcr2

Role of Suppressor of Cytokine Signaling 2 during the development and resolution of an experimental arthritis

2022 ◽  
pp. 104476
Author(s):  
Allysson Cramer ◽  
Izabela Galvão ◽  
Nathália Venturini de Sá ◽  
Paulo Gaio ◽  
Natália Fernanda de Melo Oliveira ◽  
...  
Keyword(s):  
Experimental Arthritis ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

Abstract 026: Role of Tank in the Regulation of Pathological Cardiac Hypertrophy

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hongliang Li ◽  
Peng Zhang
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Akt Inhibitor ◽  
Aortic Banding ◽  
Pathological Cardiac Hypertrophy

TRAF associated NF-κB activator (TANK) is adaptor protein which was identified as a negative regulator of TRAF-, TBK1- and IKKi-mediated signal transduction through its interaction with them. Besides its important roles in the regulation of immune response, it has been reported that TANK contributes to the development of autoimmune nephritis and osteoclastogenesis. However, its functions in cardiovascular diseases especially cardiac hypertrophy is largely unknown. In the present study, we interestingly observed that TNAK expression is increased by 240% in human hypertrophic cardiomyopathy(HCM)tissue and 320% in mouse hypertrophic heart after aortic banding (AB), indicating that TANK may be involved in the pathogenesis of this diseases. Subsequently, cardiac-specific TANK knockout (TANK-KO) and transgenic(TANK-TG)mice were generated and subjected to AB for 4 to 8 weeks. Our results demonstrated that TANK deficiency prevented against cardiac hypertrophy and fibrosis induced by pressure overload,as evidenced by that the cardiomyocytes enlargement and fibrosis formation was reduced by about 34% and 43% compared with WT mice, respectively. Conversely, TANK-TG mice showed an aggravated effect on cardiac hypertrophy in response to pressure overload with 36% and 47% increase of cardiomyocytes enlargement and fibrosis formation compared with non-transgenic mice. More importantly, in vitro experiments further revealed that TANK overexpression which was mediated by adenovirus in the cardiomyocytes dramatically increased the cell size and the expression of hypertrophic markers, whereas TANK knockdown had an opposite function. Mechanistically, we discovered that AKT signaling was activated (230%) in the hearts of TANK-TG mice, while being greatly reduced in TNAK-KO hearts after aortic banding. Moreover, blocking AKT/GSK3β signaling with a pharmacological AKT inhibitor reversed cardiac dysfunction of TANK-TG mice. Collectively, our data show that TNAK acts as a novel regulator of pathological cardiac hypertrophy and may be a promising therapeutic targets.

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