scholarly journals Role of Cardiac- and Myeloid-MyD88 Signaling in Endotoxin Shock

2014 ◽  
Vol 121 (6) ◽  
pp. 1258-1269 ◽  
Author(s):  
Yan Feng ◽  
Lin Zou ◽  
Chan Chen ◽  
Dan Li ◽  
Wei Chao
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Endotoxin Shock ◽  
Endotoxin Challenge ◽  
Cardiac Inflammation ◽  
Gene And Protein Expression ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor ◽  
Oxide Synthase

Abstract Background: Myeloid differentiation factor 88 (MyD88) is an adaptor molecule critical for host innate immunity. Studies have shown that signaling via MyD88 contributes to cytokine storm, cardiac dysfunction, and high mortality during endotoxin shock. However, the specific contribution of MyD88 signaling of immune and cardiac origins to endotoxin shock remains unknown. Methods: Tissue-specific MyD88 deletion models: Cre-recombinase transgenic mice with α-myosin heavy chain (α-MHC) or lysozyme M promoters were cross-bred with MyD88-loxP (MyD88fl/fl) mice, respectively, to generate cardiomyocyte- (α-MHC-MyD88−/−) or myeloid-specific (Lyz-MyD88−/−) MyD88 deletion models and their respective MyD88fl/fl littermates. Endotoxin shock model: Mice were subjected to 15 mg/kg lipopolysaccharide (intraperitoneal injection). Cardiac function was measured by echocardiography and cytokines by multiplex assay and quantitative reverse transcription-polymerase chain reaction. Results: α-MHC-MyD88−/− mice had 61 and 87% reduction in MyD88 gene and protein expression in cardiomyocytes, respectively, whereas Lyz-MyD88−/− had 73 and 67% decrease, respectively, in macrophages (n = 3 per group). After lipopolysaccharide treatment, the two groups of MyD88fl/fl littermates had 46% (n = 10) and 60% (n = 15) of mortality, respectively. Both α-MHC-MyD88−/− and Lyz-MyD88−/− mice had markedly improved survival. Compared with the MyD88fl/fl littermates, Lyz-MyD88−/− mice had warmer body temperature, attenuated systemic and cardiac inflammatory cytokine production, and significantly improved cardiac function, whereas α-MHC-MyD88−/− mice had decreased myocardial inducible nitric oxide synthase induction and modestly preserved cardiac function. Conclusions: Both cardiomyocyte- and myeloid-MyD88 signaling play a role in cardiac dysfunction and mortality during endotoxin shock. Myeloid-MyD88 signaling plays a predominant role in systemic and cardiac inflammation after endotoxin challenge.

scholarly journals MyD88 and Trif Signaling Play Distinct Roles in Cardiac Dysfunction and Mortality during Endotoxin Shock and Polymicrobial Sepsis

2011 ◽  
Vol 115 (3) ◽  
pp. 555-567 ◽  
Author(s):  
Yan Feng ◽  
Lin Zou ◽  
Ming Zhang ◽  
Yan Li ◽  
Chan Chen ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Critical Role ◽  
Endotoxin Shock ◽  
Left Ventricular ◽  
Polymicrobial Sepsis ◽  
Wild Type ◽  
Endotoxin Challenge ◽  
Cardiac Depression ◽  
Cecum Ligation ◽  
Myeloid Differentiation Factor

Background Toll-like receptors (TLRs) such as TLR2, TLR4, and TLR9 contribute to the pathogenesis of polymicrobial sepsis. These TLRs signal via the common myeloid differentiation factor 88 (MyD88)-dependent pathways. TLR4 also signals through MyD88-independent but TIR domain-containing adaptor inducing interferon-β-mediated transcription factor (Trif)-dependent pathway. The role of the two signaling pathways in cardiac dysfunction during polymicrobial sepsis and endotoxin shock is unknown. Methods Sepsis was generated by cecum ligation and puncture. Mice were divided into sham and cecum ligation and puncture groups or subjected to saline or endotoxin. Left ventricular function was assessed in a Langendorff apparatus or by echocardiography. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry. Results In comparison with wild-type mice, MyD88(-/-) but not Trif(-/-) mice had markedly improved cardiac function and survival after cecum ligation and puncture. In comparison, both MyD88(-/-) and Trif(-/-) mice were protected from cardiac depression and mortality during endotoxin shock. Septic MyD88(-/-) but not Trif(-/-) mice had diminished cytokine production in serum and in peritoneal space in comparison with wild-type mice after cecum ligation and puncture. In contrast, both MyD88(-/-) and Trif(-/-) mice had attenuated serum cytokines in comparison with wild-type mice after endotoxin challenge. Neither MyD88(-/-) nor Trif(-/-) signaling had any effect on neutrophil phagocytic function or bacterial clearance at 24 h of polymicrobial sepsis. Conclusions These studies establish that MyD88 but not Trif signaling plays a critical role in mediating cardiac dysfunction, systemic inflammation, and mortality during polymicrobial sepsis. Both MyD88 and Trif are essential for cardiac depression and mortality during endotoxin shock.

scholarly journals Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1120 ◽  
Author(s):  
Manisha Gupte ◽  
Prachi Umbarkar ◽  
Anand Prakash Singh ◽  
Qinkun Zhang ◽  
Sultan Tousif ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Total Period ◽  
Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

scholarly journals The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction

2020 ◽  
Author(s):  
Liangpeng Li ◽  
Wenbin Fu ◽  
Xue Gong ◽  
Zhi Chen ◽  
Luxun Tang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
G Protein ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Beclin 1 ◽  
Receptor Kinase ◽  
G Protein Coupled

Abstract Aims G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI. Methods and results We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers. Conclusion GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

scholarly journals Epac activation inhibits IL-6-induced cardiac myocyte dysfunction

2016 ◽  
Vol 68 (1) ◽  
pp. 77-87 ◽  
Author(s):  
Huiling Jin ◽  
Takayuki Fujita ◽  
Meihua Jin ◽  
Reiko Kurotani ◽  
Yuko Hidaka ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Myocyte ◽  
Cardiac Contractility ◽  
Inhibitory Effect ◽  
Intracellular Ca ◽  
Dependent Protein ◽  
Novel Target ◽  
Oxide Synthase ◽  
Stat Pathway

Abstract Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA)-mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism. In cultured cardiac myocytes, activation of Epac attenuated the inhibitory effect of interleukin-6 on the increase of intracellular Ca2+ concentration and contractility in response to isoproterenol, most likely through inhibition of the Jak-STAT pathway via SOCS3, with subsequent changes in inducible nitric oxide synthase expression. These findings suggest a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac and its downstream pathway may be a novel target for treating cardiac dysfunction in endotoxemia.

Abstract 41: Cardiomyocyte-specific Conditional Deletion of GSK-3β Leads to Cardiac Dysfunction in a High Fat Diet Induced Obesity Model

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Manisha Gupte ◽  
Samvruta Tumuluru ◽  
Anand P Singh ◽  
Prachi Umbarkar ◽  
Qinkun Zhang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Fat Mass ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Ventricular Dysfunction ◽  
Heart Weight ◽  
High Fat ◽  
Apoptotic Protein ◽  
Gsk 3Β

Introduction: Previous studies from our group have demonstrated that cardiac myocyte glycogen synthase kinase-3’s (GSK-3) are required to maintain normal cardiac physiology. Adult mice lacking both isoforms of GSK-3 (α and β) in cardiac myocytes exhibit excessive dilatative remodeling and ventricular dysfunction ultimately leading to death. While high fat diet (HFD) induced obesity is associated with increased risk of cardiovascular disease, the specific role of cardiac GSK-3α or GSK-3β in obesity-associated cardiac dysfunction is unknown. Objective: The primary goal of the present study was to investigate the role of cardiomyocyte GSK-3β in cardiac homeostasis in HFD-induced chronic obesity model. Method: Cardiomyocyte specific-GSK-3β knock out (CM-GSK-3βKO) and wild type (WT) mice were fed either a chow (11.5% calories from fat) or high-fat (60% calories from fat) for 24 weeks. Cardiac function was accessed by non-invasive transthoracic echocardiography. Results: HFD significantly increased body weight, lean and fat mass in the WT and CM-GSK-3βKO compared to chow. However, there was no difference in body weights, lean and fat mass between the two genotypes fed either a chow or HFD. Furthermore, ventricular chamber dimensions and cardiac function were comparable between the WT and CM-GSK-3βKO mice fed a chow diet. In contrast, high fat fed CM-GSK-3βKO hearts exhibit significant cardiac hypertrophy (heart weight/tibia length ratio) and ventricular dysfunction (reduced ejection fraction (EF) and fractional shortening (FS)) compared to the WT. Interestingly cardiomyocytes from HF fed CM-GSK-3βKO exhibit structural abnormalities and increased expression of pro-apoptotic protein Bax and reduced expression of Bcl-2, an anti-apoptotic protein. Conclusion: In summary, these data suggests that cardiac GSK-3β is important in the setting of HFD-induced chronic obesity to maintain cardiac function. In the absence of GSK-3β, cardiomyocytes undergo morphometric abnormalities, excessive fat infiltration and apoptosis leading to cardiac dysfunction.

Targeted disruption of ICAM-1, P-selectin genes improves cardiac function and survival in TNF-α transgenic mice

2001 ◽  
Vol 280 (4) ◽  
pp. H1464-H1471 ◽  
Author(s):  
Ana Lia Graciano ◽  
Debora D. Bryant ◽  
D. Jean White ◽  
Jureta Horton ◽  
Neil E. Bowles ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Group Versus ◽  
Transgenic Animals ◽  
Intercellular Adhesion Molecule ◽  
Kaplan Meier ◽  
Tnf Α ◽  
Necrosis Factor

We have developed a transgenic mouse model in which tumor necrosis factor (TNF)-α is overexpressed exclusively in the heart under the regulation of the α-myosin heavy chain promoter. These animals develop chronic heart failure associated with severe leukocyte infiltration in both the atria and the ventricles. The purpose of this study was to investigate the role of adhesion molecules in mediating cardiac dysfunction in the TNF-α transgenic model. TNF-α transgenic mice were bred with mice null for intercellular adhesion molecule (ICAM)-1 and P-selectin genes to obtain a lineage of ICAM-1 and P-selectin null mice with selective overexpression of TNF-α in the heart. TNF-α transgenic animals showed marked upregulation of ICAM-1 mRNA and protein; however, P-selectin mRNA and protein remained undetectable despite chronic TNF overexpression. Cardiac function was markedly improved in the ICAM-1−/−, P-selectin−/−, TNF-α transgenic group versus the ICAM+/+, P-selectin+/+, TNF-α transgenic group. Kaplan-Meier survival curves showed statistically significant prolonged survival in the ICAM-1−/−, P-selectin−/−, TNF-α transgenic animals. These data suggest that ICAM-1 mediates at least in part the cardiac dysfunction induced by TNF-α expression by cardiac myocytes.

scholarly journals Suppression of TLR4-MyD88 signaling pathway attenuated chronic mechanical pain in a rat model of endometriosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wenliang Su ◽  
Huan Cui ◽  
Danning Wu ◽  
Jiawen Yu ◽  
Lulu Ma ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
High Mobility ◽  
Adaptor Protein ◽  
Immunofluorescent Staining ◽  
Inhibitory Peptide ◽  
Tlr4 Signaling ◽  
Innate Immunity Pathway ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor

Abstract Background As a classic innate immunity pathway, Toll-like receptor 4 (TLR4) signaling has been intensively investigated for its function of pathogen recognition. The receptor is located not only on immune cells but also on sensory neurons and spinal glia. Recent studies revealed the involvement of neuronal TLR4 in different types of pain. However, the specific role of TLR4 signaling in the pain symptom of endometriosis (EM) remains obscure. Methods The rat endometriosis model was established by transplanting uterine horn tissue into gastrocnemius. Western blotting and/or immunofluorescent staining were applied to detect high mobility group box 1 (HMGB1), TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) and MyD88 homodimerization inhibitory peptide (MIP) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on endometriosis-related pain. Results Mechanical hyperalgesia was observed at the graft site, while HMGB1 was upregulated in the implanted uterine tissue, dorsal root ganglion (DRG), and spinal dorsal horn (SDH). Compared with sham group, upregulated TLR4, MyD88, and phosphorylated NF-κB-p65 were detected in the DRG and SDH in EM rats. The activation of astrocytes and microglia in the SDH was also confirmed in EM rats. Intrathecal application of LRU and MIP alleviated mechanical pain on the graft site of EM rats, with decreased phosphorylation of NF-κB-p65 in the DRG and reduced activation of glia in the SDH. Conclusions HMGB1-TLR4-MyD88 signaling pathway in the DRG and SDH may involve in endometriosis-related hyperpathia. Blockade of TLR4 and MyD88 might serve as a potential treatment for pain in endometriosis.

Abstract 12464: Exosomes Loaded With Microrna-126 Prevents Sepsis-induced Cardiac Dysfunction in Endothelial Cell Hspa12b Deficient Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Xia Zhang ◽  
Xiaohui Wang ◽  
Tuanzhu Ha ◽  
Li Liu ◽  
He Ma ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Vascular Permeability ◽  
Adhesion Molecules ◽  
Cardiac Dysfunction ◽  
Immune Cell ◽  
Cecal Ligation ◽  
Protective Role ◽  
The Right ◽  
Fractional Shortening

We have previously shown that increased expression of endothelial heat shock protein A12B (HSPA12B) attenuates LPS-induced cardiac dysfunction. MicroRNA-126 (miR-126) specifically targets adhesion molecules in endothelial cells. This study examined the role of miR-126 in HSPA12B-induced cardioprotection in sepsis. Endothelial HSPA12B-/- (n=6) and wild type (WT, n=6) mice were subjected to cecal ligation and puncture (CLP)-induced sepsis. Sham surgery served as sham control (n=6). Cardiac function was examined by echocardiography before and 6 h after CLP. CLP sepsis significantly decreased ejection fraction (EF%) by 34.8% and fractional shortening (%FS) by 43.1% in WT mice. EF% and FS% values in HSPA12B-/- septic mice showed further decreases of 19.9% and 22.5% compared with WT septic mice. The levels of ICAM1 and VCAM1 and the infiltration of immune cells (macrophages and neutrophils) into the myocardium of HSPA12B-/- septic mice were markedly greater than WT septic mice. The vascular permeability in HSPA12B-/- septic mice was much more severe than in WT septic mice. Importantly, the levels of circulating miR-126 in HSPA12B-/- septic mice were much lower than in WT septic mice. To examine whether decreased miR-126 is responsible for cardiac dysfunction in HSPA12B-/- septic mice, we loaded exosomes with miR-126 by transfection of bone marrow stromal cells with miR-126 mimics followed by isolation of exosomes 24 hours after transfection. Scrambled miR served as the miR control (miR-control). Exosomes loaded with miR-126 or miR-control were delivered into the myocardium through the right carotid artery immediately after induction of CLP (n=5-6/group). Cardiac function was significantly improved by delivery of miR-126 into the myocardium as evidenced by increased the values of EF% (51%) and FS% (59%), when compared with HSPA12B-/- septic mice. MiR-126 delivery significantly suppressed the expression of adhesion molecules, reduced immune cell infiltration in the myocardium, and improved vascular permeability in HSPA12B-/- septic mice. Delivery of miR-control did not alter cardiac dysfunction in HSPA12B-/- septic mice. We conclude that miR-126 plays a critical protective role in endothelial HSAP12B in preservation of cardiac function in sepsis.

scholarly journals Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock

1993 ◽  
Vol 110 (1) ◽  
pp. 177-182 ◽  
Author(s):  
Christoph Thiemermann ◽  
Chin-Chen Wu ◽  
Csaba Szabó ◽  
Mauro Perretti ◽  
John R. Vane
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Tumour Necrosis Factor ◽  
Rat Model ◽  
Tumour Necrosis ◽  
Endotoxin Shock ◽  
Oxide Synthase ◽  
Necrosis Factor

scholarly journals Cardiac Expression of Human Type 2 Iodothyronine Deiodinase Increases Glucose Metabolism and Protects Against Doxorubicin-induced Cardiac Dysfunction in Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (10) ◽  
pp. 3937-3946 ◽  
Author(s):  
Eun-Gyoung Hong ◽  
Brian W. Kim ◽  
Dae Young Jung ◽  
Jong Hun Kim ◽  
Tim Yu ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Metabolism ◽  
Metabolic Effects ◽  
Iodothyronine Deiodinase ◽  
Myocardial Glucose Metabolism ◽  
Human Type

Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction in ventricular fractional shortening and resulted in more than 50% death in WT mice. In contrast, MHC-D2 mice showed increased survival rate after DOX treatment, and this was associated with a six-fold increase in myocardial glucose metabolism and improved cardiac function. Myocardial activity and expression of AMPK, GLUT1, and Akt were also elevated in MHC-D2 and WT mice following DOX treatment. Thus, our findings indicate an important role of thyroid hormone in cardiac metabolism and further suggest a protective role of glucose utilization in DOX-mediated cardiac dysfunction.

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