scholarly journals The Long Noncoding RNA Hotair Regulates Oxidative Stress and Cardiac Myocyte Apoptosis during Ischemia-Reperfusion Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Kai Meng ◽  
Jiao Jiao ◽  
Rui-Rui Zhu ◽  
Bo-Yuan Wang ◽  
Xiao-Bo Mao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Calcium Binding ◽  
Cardiac Myocyte ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis

Oxidative stress and subsequent cardiac myocyte apoptosis play central roles in the initiation and progression of myocardial ischemia-reperfusion (I/R) injury. Homeobox transcript antisense intergenic RNA (Hotair) was previously implicated in various heart diseases, yet its role in myocardial I/R injury has not been clearly demonstrated. Mice with cardiac-restricted knockdown or overexpression of Hotair were exposed to I/R surgery. H9c2 cells were cultured and subjected to hypoxia/reoxygenation (H/R) stimulation to further verify the role and underlying mechanisms of Hotair in vitro. Histological examination, molecular detection, and functional parameters were determined in vivo and in vitro. In response to I/R or H/R treatment, Hotair expression was increased in a bromodomain-containing protein 4-dependent manner. Cardiac-restricted knockdown of Hotair exacerbated, whereas Hotair overexpression prevented I/R-induced oxidative stress, cardiac myocyte apoptosis, and cardiac dysfunction. Mechanistically, we observed that Hotair exerted its beneficial effects via activating AMP-activated protein kinase alpha (AMPKα). Further detection revealed that Hotair activated AMPKα through regulating the enhancer of zeste homolog 2/microRNA-451/calcium-binding protein 39 (EZH2/miR-451/Cab39) axis. We provide the evidence that endogenous lncRNA Hotair is an essential negative regulator for oxidative stress and cardiac myocyte apoptosis in myocardial I/R injury, which is dependent on AMPKα activation via the EZH2/miR-451/Cab39 axis.

scholarly journals An Antioxidant Phytotherapy to Rescue Neuronal Oxidative Stress

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Zhihong Lin ◽  
Danni Zhu ◽  
Yongqing Yan ◽  
Boyang Yu ◽  
Qiujuan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Aqueous Extract ◽  
Ischemia Reperfusion ◽  
Brain Infarction ◽  
Reaction System ◽  
Artery Occlusion ◽  
Dependent Manner ◽  
Endogenous Antioxidant

Oxidative stress is involved in the pathogenesis of ischemic neuronal injury. A Chinese herbal formula composed ofPoria cocos(Chinese name:Fu Ling),Atractylodes macrocephala(Chinese name:Bai Zhu) andAngelica sinensis(Chinese names:Danggui, Dong quai, Donggui; Korean name:Danggwi) (FBD), has been proved to be beneficial in the treatment of cerebral ischemia/reperfusion (I/R).This study was carried out to evaluate the protective effect of FBD against neuronal oxidative stressin vivoandin vitro. Rat I/R were established by middle cerebral artery occlusion (MCAO) for 1 h, followed by 24 h reperfusion. MCAO led to significant depletion in superoxide dismutase and glutathione and rise in lipid peroxidation (LPO) and nitric oxide in brain. The neurological deficit and brain infarction were also significantly elevated by MCAO as compared with sham-operated group. All the brain oxidative stress and damage were significantly attenuated by 7 days pretreatment with the aqueous extract of FBD (250 mg kg−1, p.o.). Moreover, cerebrospinal fluid sampled from FBD-pretreated rats protected PC12 cells against oxidative insult induced by 0.2 mM hydrogen peroxide, in a concentration and time-dependent manner (IC5010.6%, ET501.2 h). However, aqueous extract of FBD just slightly scavenged superoxide anion radical generated in xanthine–xanthine oxidase system (IC502.4 mg ml−1) and hydroxyl radical generated in Fenton reaction system (IC503.6 mg ml−1). In conclusion, FBD was a distinct antioxidant phytotherapy to rescue neuronal oxidative stress, through blocking LPO, restoring endogenous antioxidant system, but not scavenging free radicals.

scholarly journals β-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis: Role of β1 Integrins

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Parthiv Amin ◽  
Mahipal Singh ◽  
Krishna Singh
Keyword(s):  
Cardiac Myocyte ◽  
Matrix Metalloproteinase 2 ◽  
Background Information ◽  
Integrin Signaling ◽  
Central Feature ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis

Increased sympathetic nerve activity to the myocardium is a central feature in patients with heart failure. Accumulation of catecholamines plays an important role in the pathogenesis of heart disease. Acting via β-adrenergic receptors (β-AR), catecholamines (norepinephrine and isoproterenol) increase cardiac myocyte apoptosis in vitro and in vivo. Specifically, β1-AR and β2-AR coupled to Gαs exert a proapoptotic action, while β2-AR coupled to Gi exerts an antiapoptotic action. β1 integrin signaling protects cardiac myocytes against β-AR-stimulated apoptosis in vitro and in vivo. Interaction of matrix metalloproteinase-2 (MMP-2) with β1 integrins interferes with the survival signals initiated by β1 integrins. This paper will discuss background information on β-AR and integrin signaling and summarize the role of β1 integrins in β-AR-stimulated cardiac myocyte apoptosis.

Abstract 406: Oxidative Stress Mediated Myocardial Lipid Dysfunction

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Manikandan Panchatcharam ◽  
Mini Chandra ◽  
Jonathan Fox ◽  
Shenuarin Bhuiyan ◽  
Wayne Orr ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Negative Regulator ◽  
Membrane Pore ◽  
Mitochondrial Superoxide ◽  
Rate Of Oxygen Consumption

Lipid phosphate phosphatases-3 control the conversion of bioactive lipid phosphates to their dephosphorylated counterparts. Oxidative stress transactivates microRNA-92a, which is a negative regulator of LPP3. We found that LPP3 expression was markedly downregulated in ischemic regions after ischemia/reperfusion (I/R) injury. We observed a similar trend in the myocardium from patients samples with acute MI at 24h. Our in vitro studies indicate that overexpression of LPP3 protects the cardiomyocyte against reactive oxygen species (ROS)-induced cardiac injury and knockout of LPP3 gene in the myocardium increases cardiac dysfunction and mortality. Using XF24 Seahorse analyzer we determined the effect of ROS on respiration in pluripotent stem cell-derived cardiomyocytes (iPSC-CM). Adding Phorbol 12-myristate 13-acetate (PMA) to these cells immediately increased oxygen consumption as compared to LPP3 overexpressed cells. This apparent increase in respiration was reversible by oligomycin, which blocks ATP synthase. The rate of oxygen consumption per cell was significantly lower in stimulated compared to LPP3 overexpressed iPSC-CM. The most noticeable difference in the O 2 consumption was found in the presence of carbonilcyanide p-trifluromethoxyphenylhydrazone (FCCP). FCCP is an inner membrane pore opener which resets the proton gradient between mitochondrial matrix and interspace, resulting in continuous transport of protons and consuming O 2 at the maximum potential. Remarkably, while the FCCP treatment increased O 2 consumption in LPP3 overexpressed cells (P<0.05), the treatment showed no effect on the O 2 consumption in the PMA stimulated alone. The result indicated that the low basal oxidative phosphorylation activity in stimulated cells was due to unusually low oxidative phosphorylation potential. To explore the free radical regulation of LPP3 overexpressed cells, superoxide anion was measured using dihydroethidium, a fluorescent cholesterol analog. The levels of superoxide radicals in PMA treated cells were consistently and significantly higher than the levels in LPP3 overexpressed cells (P<0.05). In turn, the radicals can be removed by adding MitoTEMPO (a specific scavenger of mitochondrial superoxide).

Abstract 214: S100A6 Promotes Myocyte Survival by Interacting with the Receptor for Advanced Glycation End Products and Activating Akt

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
James Tsoporis ◽  
Shehla Ruby ◽  
Thomas G Parker
Keyword(s):  
Calcium Binding ◽  
Cardiac Myocyte ◽  
Direct Interaction ◽  
Annexin V ◽  
Left Ventricular ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Cytochrome C Release ◽  
End Products ◽  
Myocyte Apoptosis

The receptor for advanced ligation end-products (RAGE) recognizes ligands from diverse families including the S100 calcium binding proteins S100A6 and S100B. In a rat model of myocardial infarction, we have reported the induction of S100B, the upregulation of S100A6 and RAGE mRNA and protein in peri-infarct left ventricular (LV) myocardium, increases in S100B and S1006 serum levels and demonstrated a direct interaction between S100B and S100A6 with RAGE in peri-infarct LV myocardium. To determine the functional role of the interaction of S100A6 and S100B with RAGE, we stimulated rat neonatal cardiac myocyte cultures transfected with a RAGE gene or a dominant-negative cytoplasmic deletion mutant of RAGE with S100B and/or S100A6 for 48 hrs. In RAGE overexpressing myocytes, although both S100 proteins induced the formation of reactive oxygen species, S100B > 10 nM induced myocyte apoptosis, as evidenced by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL), FITC annexin V flow cytometry, cytochrome C release, phosphorylation of ERK1/2 and p53, and increased activity of caspase-3, whereas S100A6 < 10 nM inhibited basal myocyte apoptosis, increased the phosphorylation of Akt and the expression of NF-κB and in combination with S100B inhibited S100B-induced myocyte apoptosis [6.3±0.9% (vehicle), 16.1±0.1.2% (S100B), 4.1±0.4% (S100A6), 6.4±1.5% (S100B+S100A6) (TUNEL positive nuclei)]. The upstream Akt blocker LY294002, inhibited the RAGE dependent anti-apoptotic effects of S100A6 on basal- and S100B-induced myocyte apoptosis. In myocytes expressing dominant-negative RAGE, the contrasting effects of S100B and S100A6 on myocyte apoptosis were absent regardless of Akt inhibition. In conclusion, in a RAGE-dependent manner, S100A6 inhibits myocyte apoptosis via Akt activation.

Abstract 484: Large Tumor Suppressor 2, A Downstream Target of Mammalian Sterile 20 Like Kinase 1, Is an Endogenous Regulator of Myocyte Size and Apoptosis in the Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yutaka Matsui ◽  
Noritsugu Nakano ◽  
Hiromitsu Takagi ◽  
Dan Shao ◽  
Shumin Gao ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Negative Regulator ◽  
Large Tumor ◽  
Specific Expression ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis ◽  
Tibia Length

Mammalian sterile 20-like kinase 1 (Mst1) plays an important role in mediating apoptosis and inhibiting hypertrophy in the heart. Mst1 forms a complex with hWW45 and Large tumor suppressor 2 (Lats2), thereby activating Lats2. Lats2 dose dependently increased apoptosis in cultured cardiac myocytes and transgenic mice with cardiac specific expression of Lats2 exhibited a cardiac dysfunction, suggesting that stimulation of Lats2 leads to increased cell death and cardiac dysfunction. In order to elucidate the function of endogenous Lats2 in the heart, we generated adenovirus harboring dominant-negative Lats2 (Ad-DN-Lats2) and transgenic mice with cardiac specific expression of dominant-negative Lats2 (Tg-DN-Lats2). Ad-DN-Lats2 prevented induction of apoptosis and inhibition of hypertrophy by Mst1 in cultured cardiac myocytes, suggesting that Lats2 mediates the function of Mst1. In Tg-DN-Lats2, both LV weight/tibia length (LVW/TL; 4.34 vs 3.68, N=9, N=7, p<0.01) and RV weight/tibia length (1.15 vs 0.88, N=9, N=7, p<0.01) were greater than in NTg. Echocardiographically determined LV function was normal in Tg-DN-Lats2 at baseline except that LV wall thickness was greater in Tg-DN-Lats2 than in NTg (LV posterior wall thickness; 0.97 vs 0.79 mm, N=10, N=7, p<0.05). Since expression of Lats2 is increased in response to pressure overload (8 fold), we examined whether upregulation of endogenous Lats2 during pressure overload works as a negative feedback mechanism for cardiac hypertrophy. Tg-DN-Lats2 mice exhibited greater LVW/TL than NTg after transverse aortic constriction (TAC) (5.9 vs 4.7 mm, N=9, N=7, p<0.05). Increases in LVW/TL (+37% vs 27%, N=9, N=7, p<0.05) and LV cross sectional area (+25% vs +16%, N=5, N=5, p<0.05) after TAC were greater in Tg-DN-Lats2 than those in NTg. Moreover, Tg-DN-Lats2 exhibited significantly lower cardiac myocyte apoptosis than NTg after TAC. These results suggest that Lats2 is a negative regulator of cardiac hypertrophy at baseline and in response to pressure overload, and a positive mediator of cardiac myocyte apoptosis under pressure overload. In conclusion, Lats2 is an evolutionarily conserved negative regulator of organ size: namely inhibiting hypertrophy while stimulating apoptosis in the heart. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

p38 and ERK1/2 MAPKs mediate the interplay of TNF-α and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis

2007 ◽  
Vol 293 (6) ◽  
pp. H3524-H3531 ◽  
Author(s):  
Sanjiv Dhingra ◽  
Anita K. Sharma ◽  
Dinender K. Singla ◽  
Pawan K. Singal
Keyword(s):  
Oxidative Stress ◽  
P38 Mapk ◽  
Cardiac Myocyte ◽  
Cell Injury ◽  
Male Rats ◽  
Tnf Α ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis ◽  
Induced Changes

It is known that TNF-α increases the production of ROS and decreases antioxidant enzymes, resulting in an increase in oxidative stress. IL-10 appears to modulate these effects. The present study investigated the role of p38 and ERK1/2 MAPKs in mediating the interplay of TNF-α and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis in Sprague-Dawley male rats. Isolated adult cardiac myocytes were exposed to TNF-α (10 ng/ml), IL-10 (10 ng/ml), and IL-10 + TNF-α ( ratio 1) for 4 h. H2O2(100 μM) as a positive control and the antioxidant Trolox (20 μmol/l) were used to confirm the involvement of oxidative stress. H2O2treatment increased oxidative stress and apoptosis; TNF-α mimicked these effects. Exposure to TNF-α significantly increased ROS production, caused cell injury, and increased the number of apoptotic cells and Bax-to-Bcl-xl ratio. This change was associated with an increase in the phospho-p38 MAPK-to-total p38 MAPK ratio and a decrease in the phospho-ERK1/2-to-total ERK1/2 ratio. IL-10 treatment by itself had no effect on these parameters, but it prevented the above-listed changes caused by TNF-α. The antioxidant Trolox modulated TNF-α-induced changes in Bax/Bcl-xl, cell injury, and MAPKs. Preexposure of cells to the p38 MAPK inhibitor SB-203580 prevented TNF-α-induced changes. Inhibition of the ERK pathway with PD-98059 attenuated the protective role of IL-10 against TNF-α-induced apoptosis. This study provides evidence in support of the essential role of p38 and ERK1/2 MAPKs in the interactive role of TNF-α and IL-10 in cardiac myocyte apoptosis.

scholarly journals Exogenous ubiquitin attenuates hypoxia/reoxygenation-induced cardiac myocyte apoptosis via the involvement of CXCR4 and modulation of mitochondrial homeostasis

2020 ◽  
Vol 98 (4) ◽  
pp. 492-501 ◽  
Author(s):  
Suman Dalal ◽  
Christopher R. Daniels ◽  
Ying Li ◽  
Gary L. Wright ◽  
Mahipal Singh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Myocyte ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Mitochondrial Homeostasis ◽  
Myocyte Apoptosis ◽  
Mitochondrial Death Pathway ◽  
Induced Apoptosis ◽  
Hypoxia Reoxygenation

Exogenous ubiquitin (UB) plays a protective role in β-adrenergic receptor-stimulated and ischemia/reperfusion (I/R)-induced myocardial remodeling. Here, we report that UB treatment inhibits hypoxia/reoxygenation (H/R)-induced apoptosis in adult rat ventricular myocytes (ARVMs). The activation of Akt was elevated, whereas the activation of glycogen synthase kinase-3β was reduced in UB-treated cells post-H/R. The level of oxidative stress was lower, whereas the number of ARVMs with polarized mitochondria was significantly greater in the UB-treated samples. ARVMs express CXCR4 with majority of CXCR4 localized in the membrane fraction. CXCR4 antagonism using AMD3100, and siRNA-mediated knockdown of CXCR4 negated the protective effects of UB. Two mutated UB proteins (unable to bind CXCR4) had no effect on H/R-induced apoptosis, activation of Akt and GSK-3β, or oxidative stress. UB treatment enhanced mitochondrial biogenesis, and inhibition of mitochondrial fission using mdivi1 inhibited H/R-induced apoptosis. Ex vivo, UB treatment significantly decreased infarct size and improved functional recovery of the heart following global I/R. Activation of caspase-9, a key player of the mitochondrial death pathway, was significantly lower in UB-treated hearts post-I/R. UB, most likely acting via CXCR4, plays a protective role in H/R-induced myocyte apoptosis and myocardial I/R injury via modulation of mitochondrial homeostasis and the mitochondrial death pathway of apoptosis.

scholarly journals Renalase as a Novel Biomarker for Evaluating the Severity of Hepatic Ischemia-Reperfusion Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Huili Li ◽  
Jianrong Guo ◽  
Hongli Liu ◽  
Yanfeng Niu ◽  
Lixia Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Models ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion ◽  
R Process

Hepatic ischemia-reperfusion (I/R) injury is a serious complication in clinical practice. However, no efficient biomarkers are available for the evaluation of the severity of I/R injury. Recently, renalase has been reported to be implicated in the I/R injury of various organs. This protein is secreted into the blood in response to increased oxidative stress. To investigate the responsiveness of renalase to oxidative stress, we examined the changes of renalase in cell and mouse models. We observed a significant increase of renalase expression in HepG2 cells in a time- and dose-dependent manner when treated with H2O2. Renalase expression also increased significantly in liver tissues that underwent the hepatic I/R process. The increased renalase levels could be efficiently suppressed by antioxidantsin vitroandin vivo. Furthermore, serum renalase levels were significantly increased in the mouse models and also efficiently suppressed by antioxidants treatment. The variation trends are consistent between renalase and liver enzymes in the mouse models. In conclusion, renalase is highly sensitive and responsive to oxidative stressin vitroandin vivo. Moreover, renalase can be detected in the blood. These properties make renalase a highly promising biomarker for the evaluation of the severity of hepatic I/R injury.

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

2013 ◽  
Vol 305 (4) ◽  
pp. F495-F509 ◽  
Author(s):  
Masayuki Ishihara ◽  
Madoka Urushido ◽  
Kazu Hamada ◽  
Tatsuki Matsumoto ◽  
Yoshiko Shimamura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Light Chain ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tubules ◽  
Dependent Manner ◽  
Renal Tubular

Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1α and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stress-induced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1α-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1α-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.

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