The Toll-Like Receptor 9 Agonist, CpG-Oligodeoxynucleotide 1826, Ameliorates Cardiac Dysfunction After Trauma-Hemorrhage

Zhang, Xia; Gao, Ming; Ha, Tuanzhu; Kalbfleisch, John H.; Williams, David L.; Li, Chuanfu; Kao, Race L.

doi:10.1097/shk.0b013e31825ce0de

Cited by 15 publications

(23 citation statements)

References 29 publications

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“…The mouse trauma-hemorrhage (TH) shock model was induced as described previously (20). Trauma was produced by soft tissue injury and hemorrhage was induced by blood withdraw from the jugular vein until the mean arterial pressure reached 35 ± 5 mm Hg (20).…”

Section: Methodsmentioning

confidence: 99%

“…Trauma was produced by soft tissue injury and hemorrhage was induced by blood withdraw from the jugular vein until the mean arterial pressure reached 35 ± 5 mm Hg (20). Briefly, male mice (~30 grams) were anesthetized with isoflurane (5.0% induction, 1.5% maintenance) and placed on a heating pad to keep body temperature around 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…A 1.5 cm thoracotomy incision was performed at the left fifth intercostal space. The left ventricular (LV) apex was then punctured with a 27-gauge needle and a pressure-volume catheter (SPR-839, Millar Instruments, Inc.) was positioned in the left ventricle via the punctured apex of the heart for continuous registration of left ventricular pressure-volume loops using the PowerLab system (AD Instruments, Inc., Colorado Springs, CO) (20). After completion of the instrumentation, blood was withdrawn from the jugular vein using a Harvard syringe pump (0.82ml/10min/30g body weight) until the mean arterial pressure (AP) reached to 35 ± 5 mm Hg and was maintained at this level at the first 10 min as indicated by the time schedule.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, we and others have reported that modulation of PI3K/Akt improves cardiac function in sepsis (18) and myocardial ischemic injury (19). TH has been reported to induce the decrease of cardiomyocyte Akt phosphorylation (17, 20). But we have previously reported that CpG-ODN significantly attenuates cardiac dysfunction following TH through activation of PI3K/Akt signaling (20).…”

Section: Introductionmentioning

confidence: 99%

“…TH has been reported to induce the decrease of cardiomyocyte Akt phosphorylation (17, 20). But we have previously reported that CpG-ODN significantly attenuates cardiac dysfunction following TH through activation of PI3K/Akt signaling (20). …”

Section: Introductionmentioning

confidence: 99%

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Toll-Like Receptor 4 Plays a Central Role in Cardiac Dysfunction During Trauma Hemorrhage Shock

Zhang¹,

Chen²,

Gao³

et al. 2014

Shock

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Cardiac dysfunction is a major consequence that contributes to the high mortality of trauma-hemorrhage (TH) patients. Recent evidence suggests that innate immune and inflammatory responses mediated by Toll-like receptors (TLRs) play a critical role in the pathophysiologic mechanisms of acute organ dysfunction during TH. This study investigated the role of TLR4 in cardiac dysfunction following TH. TLR4 deficient (TLR4−/−, n=7/group) and age-matched wild type (WT, n=8/group) mice were subjected to TH that was induced by soft tissue injury and blood withdrawal from the jugular vein to a mean arterial pressure of 35 ± 5 mm Hg. Cardiac function and mean arterial pressure were measured with a Millar system before, during and after blood withdrawal. Sham surgical operated mice served as control (WT, n=9/group; TLR4−/−, n=10/group). Cardiac function in WT mice was significantly reduced following TH. However cardiac function was well preserved in TLR4−/− mice. Administration of a TLR4 antagonist (3mg/kg) to WT mice also significantly attenuated TH-induced cardiac dysfunction. Western blot showed that either TLR4−/− or TLR4 antagonist markedly attenuated TH-induced decreases in the levels of phosphorylated-Akt in myocardium. In addition, inhibition of TLR4 attenuated TH-induced myocardial NF-κB binding activity as well as lung MPO activity and TNFα production. The data indicate that TLR4 plays a central role in TH-induced cardiac dysfunction. TLR4 deficiency or TLR4 inhibition attenuated cardiac dysfunction following TH which may involve activation of the PI3K/Akt signaling and decrease of NF-κB binding activity. TLR4 antagonism may be a new and novel approach for the treatment and management of cardiac dysfunction in TH patients.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Toll-Like Receptor 4 Plays a Central Role in Cardiac Dysfunction During Trauma Hemorrhage Shock

Zhang¹,

Chen²,

Gao³

et al. 2014

Shock

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Biodegradable scaffolds for enhancing vaccine delivery

Kerr,

Johnson,

McBride

et al. 2023

Bioengineering & Transla Med

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Sustained release of vaccine components is a potential method to boost efficacy compared with traditional bolus injection. Here, we show that a biodegradable hyaluronic acid (HA)‐scaffold, termed HA cryogel, mediates sustained antigen and adjuvant release in vivo leading to a durable immune response. Delivery from subcutaneously injected HA cryogels was assessed and a formulation which enhanced the immune response while minimizing the inflammation associated with the foreign body response was identified, termed CpG‐OVA‐HAC2. Dose escalation studies with CpG‐OVA‐HAC2 demonstrated that both the antibody and T cell responses were dose‐dependent and influenced by the competency of neutrophils to perform oxidative burst. In immunodeficient post‐hematopoietic stem cell transplanted mice, immunization with CpG‐OVA‐HAC2 elicited a strong antibody response, three orders of magnitude higher than dose‐matched bolus injection. In a melanoma model, CpG‐OVA‐HAC2 induced dose‐responsive prophylactic protection, slowing the tumor growth rate and enhancing overall survival. Upon rechallenge, none of the mice developed new tumors suggesting the development of robust immunological memory and long‐lasting protection against repeat infections. CpG‐OVA‐HAC2 also enhanced survival in mice with established tumors. The results from this work support the potential for CpG‐OVA‐HAC2 to enhance vaccine delivery.

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Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia–reperfusion injury: role of RISK and SAFE pathways interaction

Zhang

et al. 2016

Apoptosis

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Recently, we demonstrated that melatonin reduced protein kinase RNA (PKR)-like ER kinase (PERK)-eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor-4 (ATF4)-mediated myocardial endoplasmic reticulum (ER) stress and apoptosis during myocardial ischemia-reperfusion (MI/R) injury. However, the underlying mechanisms are still not clear. Myocardial reperfusion injury salvage kinase (RISK) pathway as well as survivor activating factor enhancement (SAFE) pathway are two pivotal intrinsic pro-survival signaling cascades. In this study, we performed in vivo and in vitro experiment to investigate the ameliorative effect of melatonin on ER stress with a focus on RISK and SAFE pathways interaction. Male C57Bl/6 mice received melatonin (300 μg/25 g/day, 3 days before MI/R surgery; 300 μg/25 g, 25 min before the onset of ischemia) pre-treatment with or without the administration of LY294002 (a PI3K/Akt inhibitor), U0126 (an ERK1/2 inhibitor) or AG490 (a STAT3 pathway inhibitor). H9c2 cells were pre-treated with melatonin (100 μM, 8 h) in the presence or absence of LY294002, U0126 or AG490. Compared with the I/R-injured group, melatonin effectively reduced myocardial apoptosis, oxidative stress and improved cardiac function. In addition, melatonin pre-treatment also increased the phosphorylation of Akt, GSK-3β, ERK1/2 and STAT3 and reduced PERK-eIF2α-ATF4-mediated ER stress. However, these effects were blocked by LY294002, U0126 or AG490. Additionally, either LY294002 or U0126 treatment could inhibit STAT3 phosphorylation, whereas AG490 administration also reduced both Akt and ERK1/2 phosphorylation, indicating an interplay exists between RISK and SAFE pathways in melatonin's cardioprotective effect. In summary, our study demonstrates that RISK and SAFE pathways mediate the cardioprotective effect of melatonin against MI/R injury. Melatonin pre-treatment attenuates PERK-eIF2α-ATF4-mediated ER stress and apoptosis during MI/R injury via RISK and SAFE pathways interaction.

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The Toll-Like Receptor 9 Agonist, CpG-Oligodeoxynucleotide 1826, Ameliorates Cardiac Dysfunction After Trauma-Hemorrhage

Cited by 15 publications

References 29 publications

Toll-Like Receptor 4 Plays a Central Role in Cardiac Dysfunction During Trauma Hemorrhage Shock

Toll-Like Receptor 4 Plays a Central Role in Cardiac Dysfunction During Trauma Hemorrhage Shock

Biodegradable scaffolds for enhancing vaccine delivery

Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia–reperfusion injury: role of RISK and SAFE pathways interaction

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