scholarly journals Protective role of the deSUMOylating enzyme SENP3 in myocardial ischaemia-reperfusion injury

2019 ◽  
Author(s):  
Nadiia Rawlings ◽  
Laura Lee ◽  
Yasuko Nakamura ◽  
Kevin A. Wilkinson ◽  
Jeremy M Henley
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Protective Role ◽  
H9c2 Cell ◽  
Post Translational Modification ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Molecular Events ◽  
Promote Cell Survival ◽  
Whole Heart

AbstractInterruption of blood supply to the heart is a leading cause of death and disability. However, the molecular events that occur during heart ischaemia, and how these changes prime consequent cell death upon reperfusion, are poorly understood. Protein SUMOylation is a post-translational modification that has been strongly implicated in the protection of cells against a variety of stressors, including ischaemia-reperfusion. In particular, the SUMO2/3-specific protease SENP3 has emerged as an important determinant of cell survival after ischaemic infarct. Here, we used the Langendorff perfusion model to examine changes in the levels and localisation of SUMOylated target proteins and SENP3 in whole heart. We observed a 50% loss of SENP3 from the cytosolic fraction of hearts after preconditioning, a 90% loss after ischaemia and an 80% loss after ischaemia-reperfusion. To examine these effects further, we performed ischaemia and ischaemia-reperfusion experiments in the cardiomyocyte H9C2 cell line. Similar to whole hearts, ischaemia induced a decrease in cytosolic SENP3. Furthermore, shRNA-mediated knockdown of SENP3 led to an increase in the rate of cell death upon reperfusion. Together, our results indicate that cardiac ischaemia dramatically alter levels of SENP3 and suggest that this may a mechanism to promote cell survival after ischaemia-reperfusion in heart.

Kinase cascades regulating entry into apoptosis

1997 ◽  
Vol 61 (1) ◽  
pp. 33-46
Author(s):  
P Anderson
Keyword(s):  
Cell Death ◽  
Cell Surface ◽  
Cell Survival ◽  
Tyrosine Kinases ◽  
Uv Light ◽  
Apoptotic Cell ◽  
Paracrine Factors ◽  
Surface Receptors ◽  
Promote Cell Survival ◽  
Necrosis Factor

All cells are constantly exposed to conflicting environment cues that signal cell survival or cell death. Survival signals are delivered by autocrine or paracrine factors that actively suppress a default death pathway. In addition to survival factor withdrawal, cell death can be triggered by environmental stresses such as heat, UV light, and hyperosmolarity or by dedicated death receptors (e.g., FAS/APO-1 and tumor necrosis factor [TNF] receptors) that are counterparts of growth factor or survival receptors at the cell surface. One of the ways that cells integrate conflicting exogenous stimuli is by phosphorylation (or dephosphorylation) of cellular constituents by interacting cascades of serine/threonine and tyrosine protein kinases (and phosphatases). Survival factors (e.g., growth factors and mitogens) activate receptor tyrosine kinases and selected mitogen-activated, cyclin-dependent, lipid-activated, nucleic acid-dependent, and cyclic AMP-dependent kinases to promote cell survival and proliferation, whereas environmental stress (or death factors such as FAS/APO-1 ligand and TNF-alpha) activates different members of these kinase families to inhibit cell growth and, under some circumstances, promote apoptotic cell death. Because individual kinase cascades can interact with one another, they are able to integrate conflicting exogenous stimuli and provide a link between cell surface receptors and the biochemical pathways leading to cell proliferation or cell death.

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.

scholarly journals Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts

2013 ◽  
Vol 454 (2) ◽  
pp. 249-257 ◽  
Author(s):  
Qiuli Liang ◽  
Gloria A. Benavides ◽  
Athanassios Vassilopoulos ◽  
David Gius ◽  
Victor Darley-Usmar ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Mitochondrial Respiration ◽  
Energy Demand ◽  
Mammalian Target Of Rapamycin ◽  
Protective Role ◽  
Nutrient Deprivation ◽  
Autophagy Flux ◽  
Jnk Pathway ◽  
Mouse Muscle

Sirt3 (sirtuin 3) is an NAD-dependent deacetylase localized to mitochondria. Sirt3 expression is increased in mouse muscle and liver by starvation, which could protect against the starvation-dependent increase in oxidative stress and protein damage. Damaged proteins and organelles depend on autophagy for removal and this is critical for cell survival, but the role of Sirt3 is unclear. To examine this, we used Sirt3-KO (knockout) mouse embryonic fibroblast cells, and found that, under basal conditions, Sirt3-KO cells exhibited increased autophagy flux compared with WT (wild-type) cells. In response to nutrient deprivation, both WT and KO cells exhibited increased basal and ATP-linked mitochondrial respiration, indicating an increased energy demand. Both cells exhibited lower levels of phosphorylated mTOR (mammalian target of rapamycin) and higher autophagy flux, with KO cells exhibiting lower maximal mitochondrial respiration and reserve capacity, and higher levels of autophagy than WT cells. KO cells exhibit higher phospho-JNK (c-Jun N-terminal kinase) and phospho-c-Jun than WT cells under starvation conditions. However, inhibition of JNK activity in Sirt3-KO cells did not affect LC3-I (light chain 3-I) and LC3-II levels, indicating that Sirt3-regulated autophagy is independent of the JNK pathway. Caspase 3 activation and cell death are significantly higher in Sirt3-KO cells compared with WT cells in response to nutrient deprivation. Inhibition of autophagy by chloroquine exacerbated cell death in both WT and Sirt3-KO cells, and by 3-methyadenine exacerbated cell death in Sirt3-KO cells. These data suggest that nutrient deprivation-induced autophagy plays a protective role in cell survival, and Sirt3 decreases the requirement for enhanced autophagy and improves cellular bioenergetics.

scholarly journals IL-7 signaling must be intermittent, not continuous, during CD8+ T cell homeostasis to promote cell survival instead of cell death

2012 ◽  
Vol 14 (2) ◽  
pp. 143-151 ◽  
Author(s):  
Motoko Y Kimura ◽  
Leonid A Pobezinsky ◽  
Terry I Guinter ◽  
Julien Thomas ◽  
Anthony Adams ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cell Survival ◽  
Cd8 T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Promote Cell Survival

Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury

2006 ◽  
Vol 40 (6) ◽  
pp. 846-852 ◽  
Author(s):  
Lauren Valentim ◽  
Kevin M. Laurence ◽  
Paul A. Townsend ◽  
Christopher J. Carroll ◽  
Surinder Soond ◽  
...  
Keyword(s):  
Cell Death ◽  
Reperfusion Injury ◽  
Cardiac Myocytes ◽  
Autophagic Cell Death ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion

Oestrogens as apoptosis regulators in mammalian testis: angels or devils?

2015 ◽  
Vol 17 ◽  
Author(s):  
Sara Correia ◽  
Henrique J. Cardoso ◽  
José E. Cavaco ◽  
Sílvia Socorro
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Cell Survival ◽  
Cell Fate ◽  
Germ Line ◽  
Clinical Findings ◽  
Molecular Events ◽  
Mammalian Testis ◽  
Induced Apoptosis ◽  
Available Information

In the mammalian testis, spermatogenesis is a highly coordinated process of germ cell development, which ends with the release of ‘mature’ spermatozoa. The fine regulation of spermatogenesis is strictly dependent on sex steroid hormones, which orchestrate the cellular and molecular events underlying normal development of germ cells. Sex steroids actions also rely on the control of germ cell survival, and the programmed cell death by apoptosis has been indicated as a critical process in regulating the size and quality of the germ line. Recently, oestrogens have emerged as important regulators of germ cell fate. However, the beneficial or detrimental effects of oestrogens in spermatogenesis are controversial, with independent reports arguing for their role as cell survival factors or as apoptosis-inducers. The dual behaviour of oestrogens, shifting from ‘angels to devils’ is supported by the clinical findings of increased oestrogens levels in serum and intratesticular milieu of idiopathic infertile men. This review aims to discuss the available information concerning the role of oestrogens in the control of germ cell death and summarises the signalling mechanisms driven oestrogen-induced apoptosis. The present data represent a valuable basis for the clinical management of hyperoestrogenism-related infertility and provide a rationale for the use of oestrogen-target therapies in male infertility.

Polydatin post-treatment alleviates myocardial ischaemia/reperfusion injury by promoting autophagic flux

2016 ◽  
Vol 130 (18) ◽  
pp. 1641-1653 ◽  
Author(s):  
Yuanna Ling ◽  
Guiming Chen ◽  
Yi Deng ◽  
Huixiong Tang ◽  
Long Ling ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reperfusion Injury ◽  
Myocardial Ischaemia ◽  
Reactive Oxygen ◽  
Post Treatment ◽  
Autophagic Flux ◽  
Oxygen Species ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion

The present paper provides evidence that polydatin (PD) post-treatment alleviates myocardial ischaemia/reperfusion (I/R) injury by promoting autophagic flux to clear damaged mitochondria to reduce reactive oxygen species (ROS) and cell death.

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.

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