Comparison of endothelial function, O2−· and H2O2 production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice

2006 ◽  
Vol 291 (6) ◽  
pp. H2698-H2704 ◽  
Author(s):  
Nazar Labinskyy ◽  
Anna Csiszar ◽  
Zsuzsanna Orosz ◽  
Kira Smith ◽  
Aracelie Rivera ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Endothelial Function ◽  
Dna Fragmentation ◽  
Apoptotic Cell ◽  
Heat Exposure ◽  
Apoptotic Cell Death ◽  
Vascular Aging ◽  
Mole Rat ◽  
Naked Mole Rat

Vascular aging is characterized by decreased nitric oxide (NO) bioavailability, oxidative stress, and enhanced apoptotic cell death. We hypothesized that interspecies comparative assesment of vascular function among rodents with disparate longevity may offer insight into the mechanisms determining successful vascular aging. We focused on four rodents that show approximately an order of magnitude range in maximum longevity (ML). The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known (ML > 28 yr), Damara mole rats (DMRs, Cryptomys damarensis; ML ∼ 16 yr) and guinea pigs (GPs, Cavia porcellus; ML ∼ 6 yr) have intermediate longevity, whereas laboratory mice are short living (ML ∼ 3.5 yr). We compared interspecies differences in endothelial function, O2−· and H2O2 production, and resistance to apoptotic stimuli in blood vessels. Sensitivity to acetylcholine-induced, NO-mediated relaxation was smaller in carotid arteries from NMRs, GPs, and DMRs than in mouse vessels. Measurements of production of O2−· (lucigenin chemiluminescence and ethidium bromide fluorescence) and H2O2 (dichlorofluorescein fluorescence) showed that free radical production in vascular endothelial and smooth muscle cells is comparable in vessels of the three longer-living species and in arteries of shorter-living mice. In mouse arteries, H2O2 (from 10−6 to 10−3 mol/l) and heat exposure (42°C for 15–45 min) enhanced apoptotic cell death, as indicated by an increased DNA fragmentation rate and increased caspase 3/7 activity. In NMR vessels, only the highest doses of H2O2 enhanced apoptotic cell death, whereas heat exposure did not increase DNA fragmentation rate. Interspecies comparison showed there is a negative correlation between H2O2-induced apoptotic cell death and ML. Thus endothelial vasodilator function and vascular production of reactive oxygen species do not correlate with maximal lifespan, whereas increased lifespan potential is associated with an increased vascular resistance to proapoptotic stimuli.

4-hydroxynonenal induces a cellular redox status-related activation of the caspase cascade for apoptotic cell death

2000 ◽  
Vol 113 (4) ◽  
pp. 635-641 ◽  
Author(s):  
W. Liu ◽  
M. Kato ◽  
A.A. Akhand ◽  
A. Hayakawa ◽  
H. Suzuki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Dna Fragmentation ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
K562 Cells ◽  
Apoptotic Cell Death ◽  
Jurkat Cells ◽  
Substrate Peptide ◽  
Caspase Cascade

4-Hydroxynonenal (HNE), a diffusible product of lipid peroxidation, has been suggested to be a key mediator of oxidative stress-induced cell death. In this study, we partially characterized the mechanism of HNE-mediated cytotoxicity. Incubation of human T lymphoma Jurkat cells with 20–50 μM HNE led to cell death accompanied by DNA fragmentation. Western blot analysis showed that HNE-treatment induced time- and dose-dependent activation of caspase-8, caspase-9 and caspase-3. HNE-induced caspase-3 processing was confirmed by a flow cytometric demonstration of increased catalytic activity on the substrate peptide. HNE treatment also led to remarkable cleavage of poly(ADP-ribose) polymerase (PARP), which was prevented by pretreatment of cells with DEVD-FMK as a caspase-3 inhibitor. The HNE-mediated activation of caspases, cleavage of PARP and DNA fragmentation were blocked by antioxidants cysteine, N-acety-L-cysteine and dithiothreitol, but not by two other HNE-reactive amino acids lysine and histidine, or by cystine, the oxidized form of cysteine. HNE rapidly decreased levels of intracellular reduced glutathione (GSH) and its oxidized form GSSG, and these were also attenuated by the reductants. Coincubation of Jurkat cells with a blocking anti-Fas antibody prevented Fas-induced but not HNE-induced activation of caspase-3. HNE also activated caspase-3 in K562 cells that do not express functional Fas. Our results thereby demonstrate that HNE triggers oxidative stress-linked apoptotic cell death through activation of the caspase cascade. The results also suggest a possible mechanism involving a direct scavenge of intracellular GSH by HNE.

Vascular aging in the longest-living rodent, the naked mole rat

2007 ◽  
Vol 293 (2) ◽  
pp. H919-H927 ◽  
Author(s):  
Anna Csiszar ◽  
Nazar Labinskyy ◽  
Zsuzsanna Orosz ◽  
Zhao Xiangmin ◽  
Rochelle Buffenstein ◽  
...  
Keyword(s):  
Cell Death ◽  
Vascular Function ◽  
Successful Aging ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
No Donor ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Age Range

The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known [maximum lifespan potential (MLSP): >28 yr] and is a unique model of successful aging showing attenuated declines in most physiological function. This study addresses age-related changes in endothelial function and production of reactive oxygen species in NMR arteries and vessels of shorter-living Fischer 344 rats (MLSP: ∼3 yr). Rats exhibit a significant age-dependent decline in acetylcholine-induced responses in carotid arteries over a 2-yr age range. In contrast, over a 10-yr age range nitric oxide (NO)-mediated relaxation responses to acetylcholine and to the NO donor S-nitrosopencillamine (SNAP) were unaltered in NMRs. Cellular superoxide anion (O2•−) and H2O2 production significantly increased with age in rat arteries, whereas they did not change substantially with age in NMR vessels. Indicators of apoptotic cell death (DNA fragmentation rate, caspase 3/7 activity) were significantly enhanced (∼250–300%) in arteries of 2-yr-old rats. In contrast, vessels from 12-yr-old NMRs exhibited only a ∼50% increase in apoptotic cell death. In the hearts of NMRs (2 to 26 yr old), expression of endothelial NO synthase, antioxidant enzymes (Cu,Zn-SOD, Mn-SOD, catalase, and glutathione peroxidase), the NAD(P)H oxidase subunit gp91 phox, and mitochondrial proteins (COX-IV, ATP synthase, and porin, an indicator of mitochondrial mass) did not change significantly with age. Thus long-living NMRs can maintain a youthful vascular function and cellular oxidant-antioxidant phenotype relatively longer and are better protected against aging-induced oxidative stress than shorter-living rats.

scholarly journals Autophagy impairment as a key feature for acetaminophen-induced ototoxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tong Zhao ◽  
Tihua Zheng ◽  
Huining Yu ◽  
Bo Hua Hu ◽  
Bing Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Lysosomal Enzymes ◽  
Apoptotic Cell ◽  
Cell Damage ◽  
Treatment Strategies ◽  
Explant Culture ◽  
Apoptotic Cell Death ◽  
Lysosomal Dysfunction ◽  
Autophagic Degradation

AbstractMacroautophagy/autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental animals and in humans. APAP also causes ototoxicity. However, the role of autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced autophagy impairment. Inhibition of autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.

scholarly journals Hepatocyte nuclear factor-1 beta protects endometriotic cells against apoptotic cell death by up-regulating the expression of antiapoptotic genes†

2019 ◽  
Vol 101 (4) ◽  
pp. 686-694 ◽  
Author(s):  
Umma Hafsa Preya ◽  
Jeong-Hwa Woo ◽  
Youn Seok Choi ◽  
Jung-Hye Choi
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Antiapoptotic Gene ◽  
Nuclear Factor 1 ◽  
Hes Cells

Abstract The overexpression of hepatocyte nuclear factor-1 beta (HNF1β) in endometriotic lesion has been demonstrated. However, the role of HNF1β in endometriosis remains largely unknown. Human endometriotic 12Z cells showed higher level of HNF1β when compared with normal endometrial HES cells. In human endometriotic 12Z cells, HNF1β knockdown increased susceptibility to apoptotic cell death by oxidative stress, while HNF1β overexpression suppressed apoptosis. In addition, HNF1β knockdown and overexpression significantly decreased and increased, respectively, the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent antiapoptotic genes. Knockdown of the antiapoptotic genes significantly reduced the HNF1β-induced resistance against oxidative stress in 12Z cells. Furthermore, HNF1β regulated the transcriptional activity of NF-κB, and an NF-κB inhibitor suppressed the HNF1β-enhanced NF-κB-dependent antiapoptotic gene expression and the resistance of the 12Z cells against cell death. Taken together, these data suggest that HNF1β overexpression may protect endometriotic cells against oxidative damage by augmenting antiapoptotic gene expression.

scholarly journals Ginkgo biloba Prevents Oxidative Stress-Induced Apoptosis Blocking p53 Activation in Neuroblastoma Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 279 ◽  
Author(s):  
Francesco Di Meo ◽  
Rossana Cuciniello ◽  
Sabrina Margarucci ◽  
Paolo Bergamo ◽  
Orsolina Petillo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Ginkgo Biloba ◽  
Apoptotic Cell ◽  
Neuroblastoma Cells ◽  
Apoptotic Cell Death ◽  
Parp Cleavage ◽  
Egb 761 ◽  
Induced Apoptosis

Oxidative stress has been associated to neuronal cell loss in neurodegenerative diseases. Neurons are post-mitotic cells that are very sensitive to oxidative stress—especially considering their limited capacity to be replaced. Therefore, reduction of oxidative stress, and inhibiting apoptosis, will potentially prevent neurodegeneration. In this study, we investigated the neuroprotective effect of Ginkgo biloba extract (EGb 761) against H2O2 induced apoptosis in SK-N-BE neuroblastoma cells. We analysed the molecular signalling pathway involved in the apoptotic cell death. H2O2 induced an increased acetylation of p53 lysine 382, a reduction in mitochondrial membrane potential, an increased BAX/Bcl-2 ratio and consequently increased Poly (ADP-ribose) polymerase (PARP) cleavage. All these effects were blocked by EGb 761 treatment. Thus, EGb 761, acting as intracellular antioxidant, protects neuroblastoma cells against activation of p53 mediated pathway and intrinsic mitochondrial apoptosis. Our results suggest that EGb 761, protecting against oxidative-stress induced apoptotic cell death, could potentially be used as nutraceutical for the prevention and treatment of neurodegenerative diseases.

Redistribution of phosphatidylethanolamine and phosphatidylserine precedes reperfusion-induced apoptosis

1998 ◽  
Vol 274 (1) ◽  
pp. H242-H248 ◽  
Author(s):  
Nilanjana Maulik ◽  
Valerian E. Kagan ◽  
Vladimir A. Tyurin ◽  
Dipak K. Das
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Genomic Dna ◽  
High Performance ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Apoptotic Cell Death ◽  
Dna Laddering ◽  
Outer Leaflet ◽  
Induced Apoptosis

Although cardiomyocyte death and infarction associated with ischemia-reperfusion are traditionally believed to be induced via necrosis, recent studies implicated apoptotic cell death in ischemic reperfused tissue. To examine whether myocardial ischemic reperfusion injury is mediated by apoptotic cell death, isolated perfused rat hearts were subjected to 15 and 30 min of ischemia as well as 15 min of ischemia followed by 30, 90, or 120 min of reperfusion. At the end of each experiment, hearts were processed for the evaluation of apoptosis and DNA laddering. Apoptosis was studied by visualizing the apoptotic cardiomyocytes by direct fluorescence detection of digoxigenin-labeled genomic DNA using APOPTAG in situ apoptosis detection kit. DNA laddering was evaluated by subjecting the DNA obtained from cardiomyocytes to 1.8% agarose gel electrophoresis and photographed under ultraviolet illumination. In addition, high-performance thin-layer chromatography (HPTLC) of aminophospholipids labeled with 2,4,6-trinitrobenzenesulfonate was performed to evaluate phospholipid topography in cardiomyocytes. The results of our study revealed apoptotic cells only in the 90- and 120-min reperfused hearts as demonstrated by the intense fluorescence of the immunostained digoxigenin-labeled genomic DNA when observed under fluorescence microscope. None of the ischemic hearts showed any evidence of apoptosis. These results corroborated with the findings of DNA fragmentation that showed increased ladders of DNA bands in the 120-min reperfused hearts, representing integer multiples of the internucleosomal DNA length (∼180 bp). Two-dimensional HPTLC of the phospholipids obtained from the cardiomyocytes and transbilayer organization of the phosphatidylethanolamine (PE) and phosphatidylserine (PS) in the myocytes indicated translocation of both PE and PS from the inner leaflet to the outer leaflet of the membrane as early as after 20 min of ischemia. These results demonstrate that the redistribution of PS and PE precedes the apototic cell death and DNA fragmentation associated with the reperfusion of ischemic myocardium, suggesting that ischemia may trigger the signal for apoptosis although it becomes evident during reperfusion.

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