scholarly journals Evidence of necroptosis in hearts subjected to various forms of ischemic insults

2017 ◽  
Vol 95 (10) ◽  
pp. 1163-1169 ◽  
Author(s):  
Adriana Adameova ◽  
Jaroslav Hrdlicka ◽  
Adrian Szobi ◽  
Veronika Farkasova ◽  
Katarina Kopaskova ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Cell Loss ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Ischemic Insult ◽  
The Past ◽  
Tnf Α ◽  
Different Types ◽  
Promote Cell Survival

Long-lasting ischemia can result in cell loss; however, repeated episodes of brief ischemia increase the resistance of the heart against deleterious effects of subsequent prolonged ischemic insult and promote cell survival. Traditionally, it is believed that the supply of blood to the ischemic heart is associated with release of cytokines, activation of inflammatory response, and induction of necrotic cell death. In the past few years, this paradigm of passive necrosis as an uncontrolled cell death has been re-examined and the existence of a strictly regulated form of necrotic cell death, necroptosis, has been documented. This controlled cell death modality, resembling all morphological features of necrosis, has been investigated in different types of ischemia-associated heart injuries. The process of necroptosis has been found to be dependent on the activation of RIP1–RIP3–MLKL axis, which induces changes leading to the rupture of cell membrane. This pathway is activated by TNF-α, which has also been implicated in the cardioprotective signaling pathway of ischemic preconditioning. Thus, this review is intended to describe the TNF-α-mediated signaling leading to either cell survival or necroptotic cell death. In addition, some experimental data suggesting a link between heart dysfunction and the cellular loss due to necroptosis are discussed in various conditions of myocardial ischemia.

scholarly journals Death Receptor-Induced Activation of Initiator Caspase 8 Is Antagonized by Serine/Threonine Kinase PAK4

2003 ◽  
Vol 23 (21) ◽  
pp. 7838-7848 ◽  
Author(s):  
Nerina Gnesutta ◽  
Audrey Minden
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Intracellular Signaling ◽  
Death Receptor ◽  
Caspase 8 ◽  
Death Domain ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Different Types ◽  
Promote Cell Survival

ABSTRACT Normal cell growth requires a precisely controlled balance between cell death and survival. This involves activation of different types of intracellular signaling cascades within the cell. While some types of signaling proteins regulate apoptosis, or programmed cell death, other proteins within the cell can promote survival. The serine/threonine kinase PAK4 can protect cells from apoptosis in response to several different types of stimuli. As is the case for other members of the p21-activated kinase (PAK) family, one way that PAK4 may promote cell survival is by phosphorylating and thereby inhibiting the proapoptotic protein Bad. This leads in turn to the inhibition of effector caspases such as caspase 3. Here we show that in response to cytokines which activate death domain-containing receptors, such as the tumor necrosis factor and Fas receptors, PAK4 can inhibit the death signal by a different mechanism. Under these conditions, PAK4 inhibits apoptosis early in the caspase cascade, antagonizing the activation of initiator caspase 8. This inhibition, which does not require PAK4's kinase activity, may involve inhibition of caspase 8 recruitment to the death domain receptors. This role in regulating initiator caspases is an entirely novel role for the PAK proteins and suggests a new mechanism by which these proteins promote cell survival.

Anti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cells

2006 ◽  
Vol 291 (1) ◽  
pp. F67-F78 ◽  
Author(s):  
H. Thomas Lee ◽  
Mihwa Kim ◽  
Michael Jan ◽  
Charles W. Emala
Keyword(s):  
Cell Death ◽  
Proximal Tubule ◽  
Volatile Anesthetics ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Proximal Tubule Cells ◽  
Kidney Proximal Tubule ◽  
Tnf Α ◽  
Tubule Cells ◽  
Anti Inflammatory

Renal ischemia-reperfusion (IR) injury is a major clinical problem without effective therapy. We recently reported that volatile anesthetics protect against renal IR injury, in part, via their anti-inflammatory properties. In this study, we demonstrate the anti-inflammatory and antinecrotic effects of sevoflurane in cultured kidney proximal tubule cells and probed the mechanisms of sevoflurane-induced renal cellular protection. To mimic inflammation, human kidney proximal tubule (HK-2) cells were treated with tumor necrosis factor-α (TNF-α; 25 ng/ml) in the presence or absence of sevoflurane. In addition, we studied the effects of sevoflurane pretreatment on hydrogen peroxide (H2O2)-induced necrotic cell death in HK-2 or porcine proximal tubule (LLC-PK1) cells. We demonstrate that sevoflurane suppressed proinflammatory effects of TNF-α evidenced by attenuated upregulation of proinflammatory cytokine mRNA (TNF-α, MCP-1) and ICAM-1 protein and reduced nuclear translocation of the proinflammatory transcription factors NF-κB and AP-1. Sevoflurane reduced necrotic cell death induced with H2O2 in HK-2 cells as well as in LLC-PK1 cells. Sevoflurane treatment resulted in phosphorylation of prosurvival kinases, ERK and Akt, and increased de novo HSP-70 protein synthesis without affecting the synthesis of HSP-27 or HSP-32. We conclude that sevoflurane has direct anti-inflammatory and antinecrotic effects in vitro in a renal cell type particularly sensitive to injury following IR injury. These mechanisms may, in part, account for volatile anesthetics' protective effects against renal IR injury.

Reactive Oxygen Species Regulate Spontaneous and Fas-Mediated Apoptosis in SBDS-Deficient Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2036-2036
Author(s):  
Chhaya Ambekar ◽  
Bikul Das ◽  
Herman Yeger ◽  
Yigal Dror
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cell Growth ◽  
Cell Viability ◽  
Cell Survival ◽  
Annexin V ◽  
Necrotic Cell Death ◽  
Oxygen Species ◽  
Necrotic Cell

Abstract Background and hypotheses: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure, pancreatic insufficiency, and a marked propensity for myelodysplastic syndrome and leukemia. Approximately 90% of the patients have mutations in the SBDS gene, but the function of the gene is unknown. We previously showed that marrow cells from SDS patients and SBDS-deficient HeLa Cells are characterized by accelerated apoptosis, overexpression of Fas and hypersensitive to Fas stimulation. Involvement of reactive oxygen species (ROS; oxidative stress) have been shown to be related to Fas hypersensitivity and overexpression in a variety of cell types. Therefore, we hypothesized that functional deficiency in SBDS in cells that express Fas could lead to impaired ROS generation and a subsequent increase in spontaneous and Fas-mediated apoptosis and decrease in cell growth. Methods: We used shRNA-mediated SBDS-knockdown HeLa cells as a model. We investigated whether SBDS-deficiency increases ROS levels and if antioxidants can rescue the cell growth and apoptosis phenotype. To measure ROS formation cells were incubated with DCFH-DA and fluorescence measured in Gemini Spectra MAX microplate reader. Staining with annexin V and propidium iodide was done to determine apoptosis and necrotic cell death. MTT assay was used to measure cell viability. Results: ROS levels in SBDS knockdown cells were significantly increased compared to control. Apoptosis analysis by annexin V and propidium iodide showed a marked decrease in cell viability in the SBDS-knockdown cells. NAC treatment decreased ROS levels, enhanced ERK phosphorylation (pERK), improved cell viability, and decreased apoptotic and necrotic cell death. Stimulation of the Fas signaling pathway by CH-11 (activating anti-Fas antibody) and Fas ligand showed increased ROS production in SBDS Knockdown cells. CH-11 treatment showed a marked increase in apoptotic and necrotic cell death after 24 and 48hrs incubation. Cell viability decreased by 40% and 80% after 24 and 48hrs incubation with CH-11. Treatment with NAC lowered ROS levels, enhanced pERK expression, protected the cells from Fas-mediated early apoptosis and improved cell survival. Conclusion: We have demonstrated that stable loss of SBDS results in increased ROS levels, leading to apoptotic and necrotic cell death. Thus, increased baseline and Fas-stimulated ROS could result in increased sensitivity to apoptosis and necrotic cell death. NAC appeared to reverse the ROS-mediated decrease in cell survival and apoptotic cell death. Our data support the novel concept that SBDS may be a homeostatic regulator of oxidative stress

Abstract 373: Identification of Novel Anti-necrotic Factor TGN91

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jason Karch ◽  
Matthew J Brody ◽  
Onur Kanisicak ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin
Keyword(s):  
Cell Death ◽  
Transmembrane Protein ◽  
Calcium Ionophore ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Ischemic Insult ◽  
Regulated Necrosis ◽  
Mechanistic Basis ◽  
Definition Of ◽  
Golgi Network

Loss of cardiomyocytes by necrotic cell death is the direct mechanistic basis for mortality due to myocardial infarction injury, as well as ensuing heart failure associated with an array of cardiomyopathies. Further definition of the regulated necrotic pathway and identification of novel effectors will be essential in designing new therapies. To identify novel regulators of necrotic cell death we performed an unbiased lentiviral-based overexpression screen comprising of over 13,000 human cDNAs. In order to mimic an ischemic insult, the calcium ionophore ionomycin was used to induce necrotic cell death in conjunction with each individually encoded cDNA in the lentiviruses. After 24 hours of calcium overload cell viability was assessed to determine if a cDNA had a protective or maladaptive effect on necrotic cell death. One completely novel cDNA that we named Trans-Golgi Network protein 91 (TGN91) was found to be significantly protective against regulated necrosis. TGN91 is a multipass transmembrane protein that is conserved from humans to drosophila, although its function is unknown. TGN91 is most abundant in the heart compared to other tissues in the mouse and the protein resides within the Golgi. The expression of TGN91 increases in human ischemic failing hearts compared to non-ischemic failing and normal hearts. Lastly, we generated transgenic mice overexpressing TGN91 specifically in cardiomyocytes and our preliminary results suggest that these mice are protected against ischemic injury. The identification of TGN91 not only provides a novel putative regulator of the necrotic pathway, but also advocates for the Golgi as a regulatory site in necrotic cell death.

Mitochondrial aldehyde dehydrogenase attenuates hyperoxia-induced cell death through activation of ERK/MAPK and PI3K-Akt pathways in lung epithelial cells

2006 ◽  
Vol 291 (5) ◽  
pp. L966-L975 ◽  
Author(s):  
Dong Xu ◽  
Jill R. Guthrie ◽  
Sherry Mabry ◽  
Thomas M. Sack ◽  
William E. Truog
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Cell Survival ◽  
A549 Cells ◽  
Lung Epithelial Cells ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Erk Phosphorylation ◽  
Hyperoxic Exposure ◽  
Lung Epithelial

Oxygen toxicity is one of the major risk factors in the development of the chronic lung disease or bronchopulmonary dysplasia in premature infants. Using proteomic analysis, we discovered that mitochondrial aldehyde dehydrogenase (mtALDH or ALDH2) was downregulated in neonatal rat lung after hyperoxic exposure. To study the role of mtALDH in hyperoxic lung injury, we overexpressed mtALDH in human lung epithelial cells (A549) and found that mtALDH significantly reduced hyperoxia-induced cell death. Compared with control cells (Neo-A549), the necrotic cell death in mtALDH-overexpressing cells (mtALDH-A549) decreased from 25.3 to 6.5%, 50.5 to 9.1%, and 52.4 to 15.1% after 24-, 48-, and 72-h hyperoxic exposure, respectively. The levels of intracellular and mitochondria-derived reactive oxygen species (ROS) in mtALDH-A549 cells after hyperoxic exposure were significantly lowered compared with Neo-A549 cells. mtALDH overexpression significantly stimulated extracellular signal-regulated kinase (ERK) phosphorylation under normoxic and hyperoxic conditions. Inhibition of ERK phosphorylation partially eliminated the protective effect of mtALDH in hyperoxia-induced cell death, suggesting ERK activation by mtALDH conferred cellular resistance to hyperoxia. mtALDH overexpression augmented Akt phosphorylation and maintained the total Akt level in mtALDH-A549 cells under normoxic and hyperoxic conditions. Inhibition of phosphatidylinositol 3-kinase (PI3K) activation by LY294002 in mtALDH-A549 cells significantly increased necrotic cell death after hyperoxic exposure, indicating that PI3K-Akt activation by mtALDH played an important role in cell survival after hyperoxia. Taken together, these data demonstrate that mtALDH overexpression attenuates hyperoxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK/MAPK, and PI3K-Akt cell survival signaling pathways.

Oleanolic acid rich solubilized triterpene extracts from mistletoe induce apoptotic and necrotic cell death of murine B16. F10 melanoma cells

Planta Medica ◽  
2009 ◽  
Vol 75 (09) ◽  
Author(s):  
CM Strüh ◽  
S Jäger ◽  
CM Schempp ◽  
T Jakob ◽  
A Scheffler ◽  
...  
Keyword(s):  
Cell Death ◽  
Oleanolic Acid ◽  
Melanoma Cells ◽  
Necrotic Cell Death ◽  
Necrotic Cell

NADPH Oxidases: New Players in TNF-Induced Necrotic Cell Death

2007 ◽  
Vol 26 (6) ◽  
pp. 769-771 ◽  
Author(s):  
Tom Vanden Berghe ◽  
Wim Declercq ◽  
Peter Vandenabeele
Keyword(s):  
Cell Death ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Nadph Oxidases

BNip3 is a mediator of TNF-induced necrotic cell death

APOPTOSIS ◽  
2010 ◽  
Vol 16 (2) ◽  
pp. 114-126 ◽  
Author(s):  
Jee-Youn Kim ◽  
Yong-Jun Kim ◽  
Sun Lee ◽  
Jae-Hoon Park
Keyword(s):  
Cell Death ◽  
Necrotic Cell Death ◽  
Necrotic Cell
Sign in / Sign up

Export Citation Format

Share Document