TLR4 mutation and HSP60-induced cell death in adult mouse cardiac myocytes

Heiserman, James Patrick; Chen, L.; Kim, B. S.; Kim, S. C.; Tran, Alice; Siebenborn, Nina de Oliveira S.; Knowlton, Anne A

doi:10.1007/s12192-015-0577-0

Cited by 32 publications

(27 citation statements)

References 53 publications

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“…Data obtained in every field were added together to make a final data count for each slide and expressed as percentage of total cell number within the relevant fields. For in vitro cell death assessment, cell culture medium (for necrosis) and cell lysate (for apoptosis) were assayed using the Cell Death Detection ELISA PLUS per manufacturer’s protocol to measure cytoplasmic histone-associated DND fragments (momo- and oligonucleosomes) as previously described ( 30 ).…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats

Zhang

Shah

et al. 2017

Front. Immunol.

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Resolution agonists, including lipid mediators and peptides such as annexin A1 (ANXA1), are providing novel approaches to treat inflammatory conditions. Surgical trauma exerts a significant burden on the immune system that can affect and impair multiple organs. Perioperative cerebral injury after cardiac surgery is associated with significant adverse neurological outcomes such as delirium and postoperative cognitive dysfunction. Using a clinically relevant rat model of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA), we tested the pro-resolving effects of a novel bioactive ANXA1 tripeptide (ANXA1sp) on neuroinflammation and cognition. Male rats underwent 2 h CPB with 1 h DHCA at 18°C, and received vehicle or ANXA1sp followed by timed reperfusion up to postoperative day 7. Immortalized murine microglial cell line BV2 were treated with vehicle or ANXA1sp and subjected to 2 h oxygen–glucose deprivation followed by timed reoxygenation. Microglial activation, cell death, neuroinflammation, and NF-κB activation were assessed in tissue samples and cell cultures. Rats exposed to CPB and DHCA had evident neuroinflammation in various brain areas. However, in ANXA1sp-treated rats, microglial activation and cell death (apoptosis and necrosis) were reduced at 24 h and 7 days after surgery. This was associated with a reduction in key pro-inflammatory cytokines due to inhibition of NF-κB activation in the brain and systemically. Treated rats also had improved neurologic scores and shorter latency in the Morris water maze. In BV2 cells treated with ANXA1sp, similar protective effects were observed including decreased pro-inflammatory cytokines and cell death. Notably, we also found increased expression of ANXA1, which binds to NF-κB p65 and thereby inhibits its transcriptional activity. Our findings provide evidence that treatment with a novel pro-resolving ANXA1 tripeptide is neuroprotective after cardiac surgery in rats by attenuating neuroinflammation and may prevent postoperative neurologic complications.

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Section: Methodsmentioning

confidence: 99%

Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats

Zhang

Shah

et al. 2017

Front. Immunol.

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“…Studies show that blocking the apoptotic pathway may exert a protective effect against MIRI [5,6]. More recent studies have further characterized this relationship by identifying the receptor-mediated signaling and transduction pathways involved, including pathways involving toll-like receptor 4 (TLR4) [6,7]. A better molecular understanding of these apoptotic properties is a key in understanding MIRI damage and future treatment.…”

Section: Introductionmentioning

confidence: 99%

RP105 Protects Against Apoptosis in Ischemia/Reperfusion-Induced Myocardial Damage in Rats by Suppressing TLR4-Mediated Signaling Pathways

Yang

Guo

Yang

et al. 2015

Cell Physiol Biochem

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Background: Myocardial apoptosis is heavily implicated in the myocardial damage caused by ischemia-reperfusion (I/R). Toll-like receptor 4 (TLR4) is a potent inducer of these apoptotic cascades. In contrast, the radioprotective 105 kDa protein (RP105) is a specific negative regulator of TLR4 signaling pathways. However, the precise mechanisms by which RP105 inhibits myocardium apoptosis via TLR4-associated pathways during I/R is not fully understood. Methods: We utilized a rat model of myocardial ischemic reperfusion injury (MIRI). Animals were pre-treated with Ad-EGFP adenovirus, Ad-EGFP-RP105 adenovirus, saline, or nothing (sham). After three days, rats underwent a 30min left anterior descending coronary artery occlusion and a 4h reperfusion. Mycardial tissue was assessed by immunohistochemistry, TUNEL-staining, Western blot, quantitative RT-PCR, and a morphometric assay. Results: RP105 overexpression resulted in a reduction in infarct size, fewer TUNEL-positive cardiomyocytes, and a reduction in mitochondrial-associated apoptosis cascade activity. Further, RP105 overexpression repressed I/R-induced myocardial injury by attenuating myocardial apoptosis. This was mediated by inhibiting TLR4 activation and the phosphorylation of P38MAPK and the downstream transcription factor AP-1. Conclusion: RP105 overexpression leads to the de-activation of TLR4, P38MAPK, and AP-1 signaling pathways, and subsequently represses apoptotic cascades and ensuing damage of myocardial ischemic reperfusion. These findings may become the basis of a novel therapeutic approach for reducing of cardiac damage caused by MIRI.

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“…HSP60 can be released into the extracellular space including serum by various cell types [43]. Extracellular HSP60, even at low concentration, causes cardiac myocyte apoptosis and necrosis [44]. The higher mean plasma levels of HSP60 are closely associated with clinically manifest cardiovascular diseases in the patients with type 1 or type 2 diabetes [45].…”

Section: Discussionmentioning

confidence: 99%

Hypertrophic adipocyte-derived exosomal miR-802-5p contributes to insulin resistance in cardiac myocytes through targeting HSP60

Wen

et al. 2020

Preprint

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Background : Epicardial adipose tissue (EAT) is implicated in insulin resistance, which has been recognized as a strongest predictor of the development of diabetic cardiomyopathy and subsequent heart failure. However, the underlying mechanism remains incompletely understood. Herein, we investigated the effect of hypertrophic adipocytes on cardiac insulin resistance. Methods : Palmitate was used to induce hypertrophic 3T3-L1 adipocytes. Exosomes were purified from normal control or hypertrophic 3T3-L1 adipocyte-associated conditioned medium. Exosome-exposed neonatal rat ventricular myocytes (NRVMs) were treated with insulin to investigate the effects of exosomes on insulin signaling. Insulin sensitivity was evaluated by measuring insulin-stimulated Akt phosphorylation and glucose uptake. SiRNA techniques were used to downregulate protein levels and its efficiency was evaluated by western blot.Results : Hypertrophic adipocyte-derived exosomes (h-Exo) induced insulin resistance in NRVMs. Furthermore, h-Exo high-expressed miR-802-5p. Insulin sensitivity of NRVMs was impaired by miR-802-5p mimic but improved by its inhibitor. TargetScan and luciferase reporter assays revealed that heat shock protein 60 (HSP60) was a direct target of miR-802-5p. Both h-Exo and miR-802-5p mimic could downregulate HSP60 protein levels. In addition, HSP60 silencing induced insulin resistance and mitigated the insulin-sensitizing effects of adiponectin. HSP60 depletion also significantly increased the expression levels of CHOP, a marker of the unfolded protein response (UPR), and enhanced oxidative stress, accompanied by the increased phosphorylation of JNK and IRS-1 Ser307. Inhibition of both miR-802-5p and endocytosis abolished the impacts of HSP60 knockdown on the UPR and oxidative stress. Conclusion : Hypertrophic adipocyte-derived exosomal miR-802-5p caused cardiac insulin resistance in NRVMs through downregulating HSP60. These findings provide a novel mechanism by which EAT impairs cardiac function.

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TLR4 mutation and HSP60-induced cell death in adult mouse cardiac myocytes

Cited by 32 publications

References 53 publications

Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats

Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats

RP105 Protects Against Apoptosis in Ischemia/Reperfusion-Induced Myocardial Damage in Rats by Suppressing TLR4-Mediated Signaling Pathways

Hypertrophic adipocyte-derived exosomal miR-802-5p contributes to insulin resistance in cardiac myocytes through targeting HSP60

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