Glutathione Depletion by L-Buthionine-S,R-Sulfoximine Induces Apoptosis of Cardiomyocytes through Activation of PKC-δ

Kim, Young Ae; Kim, Mi Young; Jung, Yi Sook

doi:10.4062/biomolther.2013.065

Cited by 13 publications

(10 citation statements)

References 33 publications

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“…It has been reported that PKC-mediated phosphorylation of a specific serine residue on ASM (Ser508) is indispensable for its activation in response to UV irradiation or treatment with phorbol ester PMA (71,72). Recently, activation of PKC has been demonstrated in cell response to GSH depletion by BSO (73). It is conceivable that ASM could be activated by PKC-dependent phosphorylation in response to glutamate-induced GSH depletion in OLs.…”

Section: Discussionmentioning

confidence: 99%

Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis

Novgorodov

Voltin

Gooz

et al. 2018

Journal of Lipid Research

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Inhibiting the glutamate/cystine antiporter system x, a key antioxidant defense machinery in the CNS, could trigger a novel form of regulated necrotic cell death, ferroptosis. The underlying mechanisms of system x-dependent cell demise were elucidated using primary oligodendrocytes (OLs) treated with glutamate to block system x function. Pharmacological analysis revealed ferroptosis as a major contributing factor to glutamate-initiated OL death. A sphingolipid profile showed elevations of ceramide species and sphingosine that were preventable by inhibiting of an acid sphingomyelinase (ASM) activity. OL survival was enhanced by both downregulating ASM expression and blocking ASM activity. Glutamate-induced ASM activation seems to involve posttranscriptional mechanisms and was associated with a decreased GSH level. Further investigation of the mechanisms of OL response to glutamate revealed enhanced reactive oxygen species production, augmented lipid peroxidation, and opening of the mitochondrial permeability transition pore that were attenuated by hindering ASM. Of note, knocking down sirtuin 3, a deacetylase governing the mitochondrial antioxidant system, reduced OL survival. The data highlight the importance of the mitochondrial compartment in regulated necrotic cell death and accentuate the novel role of ASM in disturbing mitochondrial functions during OL response to glutamate toxicity, which is essential for pathobiology in stroke and traumatic brain injury.

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Section: Discussionmentioning

confidence: 99%

Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis

Novgorodov

Voltin

Gooz

et al. 2018

Journal of Lipid Research

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“…The characteristic features of PKCδ are a catalytic domain and a highly reactive regulatory domain, C1B, which interacts with diacylglycerol [28]. PKCδ plays important roles in the regulation of apoptosis [29]. PKC ε has a catalytic domain and two C1 domains that help direct translocation from the plasma membrane to nuclear membrane [30].…”

Section: Background Of Pkc In the Central Nervous Systemmentioning

confidence: 99%

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

Lucke‐Wold

Turner

Logsdon

et al. 2014

JAD

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Ischemic stroke and Alzheimer’s disease (AD), despite being distinct disease entities, share numerous pathophysiological mechanisms such as those mediated by inflammation, immune exhaustion, and neurovascular unit compromise. An important shared mechanistic link is acute and chronic changes in protein kinase C (PKC) activity. PKC isoforms have widespread functions important for memory, blood-brain barrier maintenance, and injury repair that change as the body ages. Disease states accelerate PKC functional modifications. Mutated forms of PKC can contribute to neurodegeneration and cognitive decline. In some cases the PKC isoforms are still functional but are not successfully translocated to appropriate locations within the cell. The deficits in proper PKC translocation worsen stroke outcome and amyloid-β toxicity. Cross talk between the innate immune system and PKC pathways contribute to the vascular status within the aging brain. Unfortunately, comorbidities such as diabetes, obesity, and hypertension disrupt normal communication between the two systems. The focus of this review is to highlight what is known about PKC function, how isoforms of PKC change with age, and what additional alterations are consequences of stroke and AD. The goal is to highlight future therapeutic targets that can be applied to both the treatment and prevention of neurologic disease. Although the pathology of ischemic stroke and AD are different, the similarity in PKC responses warrants further investigation, especially as PKC-dependent events may serve as an important connection linking age-related brain injury.

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“…155,156 For example, glutathione depletion-induced ROS generation of heart-derived H9C2 cells is triggered by caspase 3 and PKCδ activation. 157 Following ischemia, right at the onset of reperfusion, the rise in ROS 158 triggers PKCδ translocation to the mitochondria, 159 and enhances superoxide anion production, which induces mitochondrial dysfunction and subsequent potentiation of oxidative stress. This PKCδ activation can be blocked by a specific PKCδ translocation peptide inhibitor called δV1-1.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Reactive Oxygen Species at the Heart of the Matter

Kornfeld

Hwang

Disatnik

et al. 2015

Circulation Research

169

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Reactive oxygen species (ROS) have been implicated in a variety of age-related diseases including multiple cardiovascular disorders. However, translation of ROS scavengers (anti-oxidants) into the clinic has not been successful. These anti-oxidants grossly reduce total levels of cellular ROS including ROS that participate in physiological signaling. In this review, we challenge the traditional anti-oxidant therapeutic approach that targets ROS directly with novel approaches that improve mitochondrial functions to more effectively treat cardiovascular diseases.

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Glutathione Depletion by L-Buthionine-S,R-Sulfoximine Induces Apoptosis of Cardiomyocytes through Activation of PKC-δ

Cited by 13 publications

References 33 publications

Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis

Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

Mitochondrial Reactive Oxygen Species at the Heart of the Matter

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