Abstract 224: 4-phenylbutyric Protects The Heart From Heart Failure, Cardiac Rupture And Remodeling By Alleviating Cardiac Apoptosis And Fibrosis In A Mouse Model Of Myocardial Infaction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Tao Luo ◽  
Baihe Chen ◽  
Xianbao Wang ◽  
Yanping Wang ◽  
Masafumi Kitakaze ◽  
...  
Keyword(s):  
Heart Failure ◽  
Er Stress ◽  
Early Phase ◽  
Caspase 3 ◽  
Late Phase ◽  
Cardiac Rupture ◽  
Control Group ◽  
Chemical Chaperone ◽  
Protein Levels ◽  
Stress Markers

Evidences showed that endoplasmic reticulum (ER) stress has involved in cardiac hypertrophy and inhibition of ER stress exerts an effective cardioprotective effect. But little is known about the effect of ER stress inhibition on myocardial infarction (MI). The aim of this study is to investigate whether direct inhibition of ER stress by 4-phenylbutyric acid (4-PBA), an ER stress chemical chaperone, could attenuate MI induced by left coronary artery (LCA) ligation in male C57BL/6 mice. Either NaCl or 4-PBA (20 mg/kg/d) alone was intra-peritoneal injected to the mice immediately after MI for 4 weeks. Heart failure, cardiac rupture and remodeling occurred after MI. There was 52.5% vs 24% death rate in control group vs 4-PBA group during the early phase after MI (2-7 days). The survivals underwent cardiac remodeling with impaired systolic and diastolic functions at the end. The ventricular aneurysm and fibrosis were much smaller in 4-PBA group and the heart functions were improved. Western blot showed that the ER stress markers, Bax, Caspase 3, TGFβ1 and Smad 2/3 in the heart tissues of the control group were significantly increased after MI, in which Bax and Caspase 3 were increased markedly in the early phase of MI, while TGFβ1 and Smad 2/3 were increased obviously in the late phase. 4-PBA decreased those protein levels in the early and late phases of MI respectively. These findings indicate that inhibition of ER stress using 4-PBA could be an effective therapeutic agent protects the heart from post-infarcted heart failure, cardiac rupture and remodeling.

scholarly journals Selenoprotein S regulates adipogenesis through IRE1α-XBP1 pathway

2020 ◽  
Vol 244 (3) ◽  
pp. 431-443
Author(s):  
Lili Men ◽  
Junjie Yao ◽  
Shanshan Yu ◽  
Yu Li ◽  
Siyuan Cui ◽  
...  
Keyword(s):  
Er Stress ◽  
Late Phase ◽  
G1 Arrest ◽  
Mrna Levels ◽  
Protein Levels ◽  
Selenoprotein S ◽  
Stress Markers ◽  
Obese Subjects

The induction of endoplasmic reticulum (ER) stress is associated with adipogenesis, during which the inositol-requiring enzyme 1 alpha (IRE1α)-X-box-binding protein 1 (XBP1) pathway is involved. Selenoprotein S (SelS), which is an ER resident selenoprotein, is involved in ER homeostasis regulation; however, little is known about the role of SelS in regulating adipogenesis. In vivo studies showed that SelS protein levels in white adipose tissue were increased in obese subjects and high-fat diet (HFD)-fed mice. Moreover, we identified that SelS protein levels increased in the early phase of adipogenesis and then decreased in the late phase during adipogenesis. Overexpression of SelS promoted adipogenesis. Conversely, knockdown (KD) of SelS resulted in the inhibition of adipogenesis, which was related to increasing cell death, decreased mitotic clonal expansion, and cell cycle G1 arrest. In vivo studies also showed that ER stress markers (p-IRE1α/IRE1α, XBP1s, and Grp78) were significantly increased with upregulating of SelS expression in subcutaneous and visceral adipose tissues in the obese subjects and HFD-fed mice. Furthermore, in SelS KD cells, the levels of Grp78 were increased and the levels of p-IRE1α/IRE1α were unchanged , but mRNA levels of spliced XBP1 (XBP1s) produced by IRE1α-mediated splicing were decreased, suggesting a role of SelS in the modulation of IRE1α-XBP1 pathway. Moreover, inhibition of adipogenesis by SelS suppression can be rescued by overexpression of XBP1s. Thus, SelS appears to function as a novel regulator of adipogenesis through the IRE1α-XBP1 signaling pathway.

scholarly journals Amelioration of Glucolipotoxicity-Induced Endoplasmic Reticulum Stress by a “Chemical Chaperone” in Human THP-1 Monocytes

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Raji Lenin ◽  
Mariawilliam Sneha Maria ◽  
Madhur Agrawal ◽  
Jayashree Balasubramanyam ◽  
Viswanathan Mohan ◽  
...  
Keyword(s):  
Er Stress ◽  
Arterial Wall ◽  
Caspase 3 ◽  
Ros Generation ◽  
Monocyte Activation ◽  
Chemical Chaperone ◽  
Stress Markers ◽  
Atherosclerotic Lesions ◽  
Channel Expression ◽  
Underlying Causes

Chronic ER stress is emerging as a trigger that imbalances a number of systemic and arterial-wall factors and promote atherosclerosis. Macrophage apoptosis within advanced atherosclerotic lesions is also known to increase the risk of atherothrombotic disease. We hypothesize that glucolipotoxicity might mediate monocyte activation and apoptosis through ER stress. Therefore, the aims of this study are (a) to investigate whether glucolipotoxicity could impose ER stress and apoptosis in THP-1 human monocytes and (b) to investigate whether 4-Phenyl butyric acid (PBA), a chemical chaperone could resist the glucolipotoxicity-induced ER stress and apoptosis. Cells subjected to either glucolipotoxicity or tunicamycin exhibited increased ROS generation, gene and protein (PERK, GRP-78, IRE1α, and CHOP) expression of ER stress markers. In addition, these cells showed increased TRPC-6 channel expression and apoptosis as revealed by DNA damage and increased caspase-3 activity. While glucolipotoxicity/tunicamycin increased oxidative stress, ER stress, mRNA expression of TRPC-6, and programmed the THP-1 monocytes towards apoptosis, all these molecular perturbations were resisted by PBA. Since ER stress is one of the underlying causes of monocyte dysfunction in diabetes and atherosclerosis, our study emphasize that chemical chaperones such as PBA could alleviate ER stress and have potential to become novel therapeutics.

scholarly journals Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus

2017 ◽  
Vol 59 (1) ◽  
pp. 81-92 ◽  
Author(s):  
Long The Nguyen ◽  
Sonia Saad ◽  
Yi Tan ◽  
Carol Pollock ◽  
Hui Chen
Keyword(s):  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Er Stress ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Mrna Level ◽  
Metabolic Stress ◽  
High Fat ◽  
Chemical Chaperone ◽  
Protein Levels

Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.

scholarly journals Attenuation of endoplasmic reticulum stress by caffeine ameliorates hyperoxia-induced lung injury

2017 ◽  
Vol 312 (5) ◽  
pp. L586-L598 ◽  
Author(s):  
Ru-Jeng Teng ◽  
Xigang Jing ◽  
Teresa Michalkiewicz ◽  
Adeleye J. Afolayan ◽  
Tzong-Jin Wu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lung Injury ◽  
Er Stress ◽  
Saline Control ◽  
Sprague Dawley ◽  
Chemical Chaperone ◽  
Stress Markers ◽  
Rat Pups ◽  
Caffeine Treatment ◽  
Downstream Effectors

Rodent pups exposed to hyperoxia develop lung changes similar to bronchopulmonary dysplasia (BPD) in extremely premature infants. Oxidative stress from hyperoxia can injure developing lungs through endoplasmic reticulum (ER) stress. Early caffeine treatment decreases the rate of BPD, but the mechanisms remain unclear. We hypothesized that caffeine attenuates hyperoxia-induced lung injury through its chemical chaperone property. Sprague-Dawley rat pups were raised either in 90 (hyperoxia) or 21% (normoxia) oxygen from postnatal day 1 (P1) to postnatal day 10 (P10) and then recovered in 21% oxygen until P21. Caffeine (20 mg/kg) or normal saline (control) was administered intraperitoneally daily starting from P2. Lungs were inflation-fixed for histology or snap-frozen for immunoblots. Blood caffeine levels were measured in treated pups at euthanasia and were found to be 18.4 ± 4.9 μg/ml. Hyperoxia impaired alveolar formation and increased ER stress markers and downstream effectors; caffeine treatment attenuated these changes at P10. Caffeine also attenuated the hyperoxia-induced activation of cyclooxygenase-2 and markers of apoptosis. In conclusion, hyperoxia-induced alveolar growth impairment is mediated, in part, by ER stress. Early caffeine treatment protects developing lungs from hyperoxia-induced injury by attenuating ER stress.

scholarly journals Ling-Gui-Zhu-Gan Decoction Protects H9c2 Cells against H2O2-Induced Oxidative Injury via Regulation of the Nrf2/Keap1/HO-1 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Xiang Wang ◽  
Tongjuan Tang ◽  
Mengting Zhai ◽  
Ruirui Ge ◽  
Liang Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Stress Response ◽  
Caspase 3 ◽  
Underlying Mechanism ◽  
Oxidative Stress Response ◽  
Control Group ◽  
H9c2 Cells ◽  
Model Group ◽  
Blank Control Group

Objectives. Ling-Gui-Zhu-Gan decoction (LGZGD) is a potentially effective treatment for heart failure, and it showed significant anti-inflammatory potential in our previous studies. However, its ability to ameliorate heart failure through regulation of oxidative stress response is still unknown. This study was aimed to investigate the protective effect of LGZGD-containing serum on H2O2-induced oxidative injury in H9c2 cells and explore the underlying mechanism. Methods. Eighteen rats were randomly divided into two groups: the blank control group and LGZGD group. The LGZGD group rats were administrated with 8.4 g/kg/d LGZGD for seven consecutive days through gavage, while the blank control group rats were given an equal volume of saline. The serum was extracted from all the rats. To investigate the efficacy and the underlying mechanism of LGZGD, we categorized the H9c2 cells into groups: the control group, model group, normal serum control (NSC) group, LGZGD group, LGZGD + all-trans-retinoic acid (ATRA) group, and ATRA group. Malonedialdehyde (MDA) and superoxide dismutase (SOD) were used as markers for oxidative stress. Dichlorodihydrofluorescin diacetate (DCFH-DA) staining was used to measure the levels of reactive oxygen species (ROS). The apoptosis rate was detected using flow cytometry. The expression levels of pro-caspase-3, cleaved-caspase-3, Bcl-2, Bax, Keap1, Nrf2, and HO-1 were measured using western blotting. The mRNA levels of Keap1, Nrf2, and HO-1 were measured using RT-qPCR. Results. The LGZGD attenuated injury to H9c2 cells and reduced the apoptosis rate. It was also found to upregulate the SOD activity and suppress the formation of MDA and ROS. The expression levels of pro-caspase-3 and Bcl-2 were significantly increased, while those of cleaved-caspase-3 and Bax were decreased in the LGZGD group compared with the model group. As compared with the model group, the LGZGD group demonstrated decreased Keap1 protein expression and significantly increased Nrf2 nuclear expression and Nrf2-mediated transcriptional activity. ATRA was found to reverse the LGZGD-mediated antioxidative and antiapoptotic effect on injured H9c2 cells induced by H2O2. Conclusion. Our results demonstrated that LGZGD attenuated the H2O2-induced injury to H9c2 cells by inhibiting oxidative stress and apoptosis via the Nrf2/Keap1/HO-1 pathway. These observations suggest that LGZGD might prevent and treat heart failure through regulation of the oxidative stress response.

scholarly journals Endoplasmic reticulum stress regulates cell injury in lipopolysaccharide-induced nerve cells

2020 ◽  
Vol 48 (9) ◽  
pp. 030006052094976
Author(s):  
Min Li ◽  
Ying Zhang ◽  
Jixing Wang
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Viability ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Cell Injury ◽  
Cell Counting ◽  
Tunel Staining ◽  
Dependent Manner ◽  
Stress Markers

Objective Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and excessive endoplasmic reticulum (ER) stress is closely correlated with the cell injury caused by sepsis. This study aimed to analyze the possible role of ER stress in SAE cell models. Methods PC12 and MES23.5 cells were treated with increasing concentrations of lipopolysaccharides (LPS). The Cell Counting Kit-8 assay was used to detect cell viability and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed to assess cell apoptosis. In addition, the protein expression levels of ER stress markers [GRP78, CHOP, inositol-requiring enzyme 1 (IRE1), and PKR-like ER kinase (PERK)] and apoptosis-related proteins (Bax, Bcl-2, caspase-3, and cleaved caspase-3) were analyzed using western blotting. Results LPS treatment activated ER stress markers in both the PC12 and MES23.5 cells. The overexpression of GRP78 significantly reduced cell viability and enhanced cell apoptosis in a time-dependent manner. An ER stress inhibitor, 4-PBA, significantly enhanced cell viability and inhibited the cell apoptosis induced by LPS. Therefore, an enhanced unfolded protein response (UPR) and UPR suppression may regulate cell apoptosis. Conclusions UPR was shown to be involved in regulating LPS-induced neuron injury. UPR could be a potential therapeutic target in SAE.

scholarly journals Effects of Resistance, Endurance, and Concurrent Exercise on Oxidative Stress Markers and the Histological Changes of Intestine After Morphine Withdrawal in Rats

2018 ◽  
Vol 6 (2) ◽  
pp. 44-49
Author(s):  
Iraj Salehi ◽  
Ebrahim Zarrinkalam‎ ◽  
Fatemeh Mirzaei ◽  
Ebrahim Abbasi Oshaghi ◽  
Kamal Ranjbar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Morphological Changes ◽  
Morphine Withdrawal ◽  
Morphological Alteration ◽  
Control Group ◽  
Oxidative Stress Markers ◽  
Histological Changes ◽  
Protein Levels ◽  
Stress Markers ◽  
Concurrent Exercise

Objectives: The aim of this study was to evaluate the effects of resistance, endurance, and concurrent exercise on oxidative stress markers and histological changes of the intestine after morphine withdrawal in rats. Methods: A total of 30 male Wistar rats were randomly divided into 5 groups (n=6) including healthy control, withdrawal (rat received morphine for 21 days and 8 weeks of withdrawal period), withdrawal + endurance exercises, withdrawal + resistance exercises, and withdrawal + concurrent exercises. The rats practiced endurance, resistance, and concurrent exercises for 10 weeks. Then, their intestines were removed and used for biochemical and histological analysis. Next, several factors were measured such as total protein levels, malondialdehyde (MDA), reduced glutathione (GSH), total antioxidant capacity (TAC), and total oxidant status (TOS). Finally, the morphological alteration of intestine was examined under the light microscope. Results: Morphine withdrawal significantly increased the levels of MDA in the intestine of withdrawal rats compared to those of the control group while endurance, resistance, and concurrent exercise reduced the MDA levels in the intestine. In addition, morphine withdrawal led to a decrease in TAC and GSH levels in the intestine compared to control rats whereas endurance, resistance, and concurrent exercise noticeably increased TAC and GSH levels. Interestingly, the change in the concurrent group was more significant. Moreover, the levels of TOS demonstrated a significant increase in the addicted rat as compared to the control group. Conversely, endurance, resistance, and concurrent exercise significantly decreased TOS levels and the reduction was more significant in the concurrent group. Finally, the intestine of withdrawal rat was morphologically abnormal while it restored by the exercise. Conclusion: Overall, endurance, resistance, and concurrent exercise significantly normalized oxidative stress and the morphological changes of the intestine in withdrawal rats.

scholarly journals Insulin-like Growth Factor-1 Receptor (IGF-1R) As a Potential Therapeutic Target in Diffuse Large B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4828-4828
Author(s):  
Xiangxiang Zhou ◽  
Lingyun Geng ◽  
Xinyu Li ◽  
Peipei Li ◽  
Kang Lu ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
Annexin V ◽  
B Cell Lymphoma ◽  
Control Group ◽  
Protein Levels ◽  
Proliferation And Apoptosis ◽  
Dose Dependent Decrease

Abstract Introduction : The receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) is dysregulated in various tumor entities and hematological malignancies including chronic lymphocytic leukemia and mantle cell lymphoma. The implication of IGF1R in the development and progression of cancer has led to its current evaluation in clinical trials as a potential therapeutic target for solid tumors. However, its functional significance in diffuse large B-cell lymphoma (DLBCL) remains poorly characterized. We hypothesized that IGF1R plays a key role in the pathogenesis and progression of DLBCL. In this present study, we evaluated the expression and function of IGF1R in both B cell lines and DLBCL tissues, as well as assessed the proliferation and apoptosis of DLBCL cells when treated with IGF-1R inhibitor, AG1024. Methods : Expression of IGF1R in B-cell lymphoma cell lines (LY1, LY8, Mino, Jeko-1, and SP53) was evaluated by Western blotting. Peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers with informed consents. Blood samples and araffin-embedded tissues from 30 initial-diagnosed DLBCL patients prior to therapeutic interventions as a study group, and from 15 patients with reactive hyperplasia lymphnode as a control group were collected with informed consents. Immunohistochemisty (IHC) was conducted to assess the expression of IGF-1R in lymphoma tissues. Correlations between IGF1R expression and the clinical characteristics of DLBCL patients were further analyzed. DLBCL cell lines (LY1 and LY8) were treated with an IGF1R specific small molecular inhibitor, AG1024, cell proliferation was analyzed by cell counting kit (CCK-8). Effects of inhibitor or stimulator on the apoptosis of LY1 and LY8 cells were assessed by Annexin-V/PI and Annexin-V/7AAD, respectively. Expression of apoptosis-related protein, including Caspase-3 and Mcl-1, was evaluated by western blotting. Protein levels of downstream targets of IGF-1 signaling were also detected. Results : Significantly upregulation of both phoaphprylated and total IGF1R protein levels were found in B-cell lymphoma cells (LY1, LY8, Mino, Jeko-1 and SP53) (Fig 1.A). IHC was conducted and revealed significantly enhancement of IGF1R expression in DLBCL patients (Fig 1.B). Among the included DLBCL patients and control group with inreactive hyperplastic lymphadenitis, the positive rate of IGF1R was 90% and 20%, respectively. We then investigated the function of IGF1R inhibitors on the proliferation and apoptosis of DLBCL cells. LY8 cells were treated with different doses of AG1024 at 24-96 hours. Cell proliferation was inhibited by 60% when treated with AG1024 at the concentration of 15µM for 72-hours (Fig 1.C). Culture of LY1 and LY8 cells in the presence of 10µM and 15µM AG1024 concentration for 24-hours resulted in 13% (p<0.05) and 33% (p<0.001) cell apoptosis, respectively (Fig 1.D). Inhibition of IGF1R by AG1024 also resulted in induction of cleaved-Caspase-3, as well as reduction of Mcl-1(Fig 1.E-F). In order to investigate the mechanisms involved in the dysregultaion of IGF1R in DLBCL, LY8 cells were treated with 5 to 15 µM AG1024, the results revealed that AG1024 caused a dose-dependent decrease in the levels of phosphorylated IGF1R, AKT and ERK (Fig 1.G). Treatment of LY8 cells with recombinant human IGF-1 led to enhanced phosporylation levels of IGF1R, AKT and ERK (Fig 1.H). Conclusion s: Our investigation observed that expression levels of IGF-1R were up-regulated in both B-cell lymphoma cells and DLBCL tissues. DLBCL cells treated with IGF-1R inhibitor, AG1024, revealed reduced proliferation and increased apoptosis rate. In addition, induction of cleaved-Caspase-3 was also found in LY1 treated with AG1024. AG1024 caused a dose-dependent decrease in the phosphorylation levels of IGF1R, AKT and ERK. This study suggests that IGF1R could be a potential molecular target for the treatment of DLBCL. The IGF-1R inhibitor is a promising therapeutic approach for DLBCL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Seipin Deficiency Accelerates Heart Failure Due to Calcium Handling Abnormalities and Endoplasmic Reticulum Stress in Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoyue Wu ◽  
Xuejing Liu ◽  
Huan Wang ◽  
Zihao Zhou ◽  
Chengzhi Yang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Diastolic Heart Failure ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Related Factors ◽  
Current Decay ◽  
Protein Levels

Seipin deficiency can induce hypertrophic cardiomyopathy and heart failure, which often leads to death in humans. To explore the effects and the possible mechanisms of Seipin deficiency in myocardial remodeling, Seipin knockout (SKO) mice underwent transverse aortic constriction (TAC) for 12 weeks. We found a more severe left ventricular hypertrophy and diastolic heart failure and increases in inflammatory cell infiltration, collagen deposition, and apoptotic bodies in the SKO group compared to those in the wild type (WT) group after TAC. Electron microscopy also showed a more extensive sarcoplasmic reticulum expansion, deformation of microtubules, and formation of mitochondrial lesions in the cardiomyocytes of SKO mice than in those of WT mice after TAC. Compared with the WT group, the SKO group showed increases in endoplasmic reticulum (ER) stress-, inflammation-, and fibrosis-related gene expression, while calcium ion-related factors, such as Serca2a and Ryr, were decreased in the SKO group after TAC. Increased levels of the ER stress-related protein GRP78 and decreased SERCA2a and P-RYR protein levels were detected in the SKO group compared with the WT group after TAC. Slowing of transient Ca2+ current decay and an increased SR Ca2+ content in myocytes were detected in the cardiomyocytes of SKO mice. Adipose tissue transplantation could not rescue the cardiac hypertrophy after TAC in SKO mice. In conclusion, we found that Seipin deficiency could promote cardiac hypertrophy and diastolic heart failure after TAC in mice. These changes may be related to the impairment of myocardial calcium handling, ER stress, inflammation, and apoptosis.

scholarly journals Complement Regulation in Human Tenocytes under the Influence of Anaphylatoxin C5a

2021 ◽  
Vol 22 (6) ◽  
pp. 3105
Author(s):  
Sandeep Silawal ◽  
Benjamin Kohl ◽  
Jingjian Shi ◽  
Gundula Schulze-Tanzil
Keyword(s):  
Gene Expression ◽  
Early Phase ◽  
Intermediate Phase ◽  
Late Phase ◽  
Tendon Healing ◽  
Hamstring Tendon ◽  
Inflammatory Factors ◽  
Control Group ◽  
Related Factors ◽  
Anaphylatoxin C5a

A central part of the complement system, the anaphylatoxin C5a was investigated in this study to learn its effects on tenocytes in respect to understanding the potential expression of other crucial complement factors and pro-inflammatory mediators involved in tendinopathy. Human hamstring tendon-derived tenocytes were treated with recombinant C5a protein in concentrations of 25 ng/mL and 100 ng/mL for 0.5 h (early phase), 4 h (intermediate phase), and 24 h (late phase). Tenocytes survival was assessed after 24 h stimulation by live-dead assay. The gene expression of complement-related factors C5aR, the complement regulatory proteins (CRPs) CD46, CD55, CD59, and of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 was monitored using qPCR. Tenocytes were immunolabeled for C5aR and CD55 proteins. TNFα production was monitored by ELISA. Tenocyte survival was not impaired through C5a stimulation. Interestingly, the gene expression of C5aR and that of the CRPs CD46 and CD59 was significantly reduced in the intermediate and late phase, and that of TNFα only in an early phase, compared to the control group. ELISA analysis indicated a concomitant not significant trend of impaired TNFα protein synthesis at 4 h. However, there was also an early significant induction of CD55 and CD59 mediated by 25 ng/mL anaphylatoxin C5a. Hence, exposure of tenocytes to C5a obviously evokes a time and concentration-dependent response in their expression of complement and pro-inflammatory factors. C5a, released in damaged tendons, might directly contribute to tenocyte activation and thereby be involved in tendon healing and tendinopathy.

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