PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury

Nagoshi, Tomohisa; Mizutani, Takashi; Aoyama, Takuma; Leri, Annarosa; Anversa, Piero; Li, Ling; Ogawa, Wataru; Monte, Federica del; Gwathmey, Judith K.; Grazette, Luanda; Hemmings, Brian A.; Kass, David A.; Champion, Hunter C.; Rosenzweig, Anthony

doi:10.1172/jci23073

Cited by 218 publications

(204 citation statements)

References 57 publications

(76 reference statements)

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“…The latter observation suggests that loss of PTEN may contribute to neurodegeneration despite the fact of elevated Akt phosphorylation. It is not clear whether the Akt signaling pathway is impaired in Alzheimer disease brains because chronic Akt activation may be detrimental to neurons as exemplified in other studies (56). Alternatively, the observed increase in phospho-Akt in the Alzheimer disease brains does not indicate increased Akt activation and signaling as suggested by a recent report showing that increased phospho-Akt is asso-4 Y.-D. Kwak, unpublished data.…”

Section: Discussionmentioning

confidence: 90%

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

Kwak

Wang

Pan

et al. 2010

Journal of Biological Chemistry

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The contribution of zinc-mediated neuronal death in the process of both acute and chronic neurodegeneration has been increasingly appreciated. Phosphatase and tensin homologue, deleted on chromosome 10 (PTEN), the major tumor suppressor and key regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, plays a critical role in neuronal death in response to various insults. NEDD4-1-mediated PTEN ubiquitination and subsequent degradation via the ubiquitin proteosomal system have recently been demonstrated to be the important regulatory mechanism for PTEN in several cancer types. We now demonstrate that PTEN is also the key mediator of the PI3K/Akt pathway in the neuronal response to zinc insult. We used primary cortical neurons and neuroblastoma N2a cells to show that zinc treatment results in a reduction of the PTEN protein level in parallel with increased NEDD4-1 gene/protein expression. The reduced PTEN level is associated with an activated PI3K pathway as determined by elevated phosphorylation of both Akt and GSK-3 as well as by the attenuating effect of a specific PI3K inhibitor (wortmannin). The reduction of PTEN can be attributed to increased protein degradation via the ubiquitin proteosomal system, as we show NEDD4-1 to be the major E3 ligase responsible for PTEN ubiquitination in neurons. Moreover, PTEN and NEDD4-1 appear to be able to counter-regulate each other to mediate the neuronal response to zinc. This reciprocal regulation requires the PI3K signaling pathway, suggesting a feedback loop mechanism. This study demonstrates that NEDD4-1-mediated PTEN ubiquitination is crucial in the regulation of PI3K/Akt signaling by PTEN during the neuronal response to zinc, which may represent a common mechanism in neurodegeneration.Zinc is increasingly recognized as an important molecule that plays both physiological and pathological roles in a variety of biological processes. The role of zinc in the central nervous system has also been discovered over the past 2 decades, as a neurotransmitter in modulating synaptic plasticity (1, 2). Although zinc is selectively stored in the pre-synaptic vesicles of a specific type of neuron, sequestered or tightly bound to cellular compartments, it can be rapidly released in response to extracellular signals. The same neurons also secrete glutamate and are the so-called "gluzinergic" neurons found primarily in the mammalian cerebral cortex. Neurons store up to 300 M free zinc in their termini (3) and release it through several types of cation channels (e.g. N-methyl-D-aspartic acid receptors) when they are depolarized, reaching high concentrations that are known to cause acute neuronal death. Together with glutamate, zinc mediates excitotoxicity, as manifested in acute brain injuries, ischemia, and seizures (4, 5). Zinc is also implicated in chronic neurodegenerative diseases such as Alzheimer disease via direct chelation with the amyloid precursor protein, thereby modulating its processing and generating oxidative stress (6).In cortical cell cultures, 100 M zinc, with ...

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Section: Discussionmentioning

confidence: 90%

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

Kwak

Wang

Pan

et al. 2010

Journal of Biological Chemistry

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“…Meanwhile, reports have also focused on the roles of the AKT signaling pathway in cardiac hypertrophy, and some reports supported the opinion that activation of the AKT signaling pathway could inhibit cardiomyocyte apoptosis and promote heart function 23, 24, 25. Nagoshi et al25 posited that the acute activation of AKT is cardioprotective and can reduce infarction size and cardiac dysfunction after ischemia–reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

“…Nagoshi et al25 posited that the acute activation of AKT is cardioprotective and can reduce infarction size and cardiac dysfunction after ischemia–reperfusion injury. Condorelli et al26 observed that cardiac‐specific AKT overexpression significantly increased cardiomyocyte size, which was associated with increased systolic function.…”

Section: Discussionmentioning

confidence: 99%

C‐C Motif Chemokine Receptor 9 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction

Xu¹,

Mei

Liu³

et al. 2016

JAHA

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BackgroundMaladaptive cardiac hypertrophy is a major risk factor for heart failure, which is the leading cause of death worldwide. C‐C motif chemokine receptor 9 (CCR9), a subfamily of the G protein–coupled receptor supergene family, has been highlighted as an immunologic regulator in the development and homing of immune cells and in immune‐related diseases. Recently, CCR9 was found to be involved in the pathogenesis of other diseases such as cardiovascular diseases; however, the effects that CCR9 exerts in cardiac hypertrophy remain elusive.Methods and ResultsWe observed significantly increased CCR9 protein levels in failing human hearts and in a mouse or cardiomyocyte hypertrophy model. In loss‐ and gain‐of‐function experiments, we found that pressure overload–induced hypertrophy was greatly attenuated by CCR9 deficiency in cardiac‐specific CCR9 knockout mice, whereas CCR9 overexpression in cardiac‐specific transgenic mice strikingly enhanced cardiac hypertrophy. The prohypertrophic effects of CCR9 were also tested in vitro, and a similar phenomenon was observed. Consequently, we identified a causal role for CCR9 in pathological cardiac hypertrophy. Mechanistically, we revealed a lack of difference in the expression levels of mitogen‐activated protein kinases between groups, whereas the phosphorylation of AKT/protein kinase B and downstream effectors significantly decreased in CCR9 knockout mice and increased in CCR9 transgenic mice after aortic binding surgery.ConclusionsThe prohypertrophic effects of CCR9 were not attributable to the mitogen‐activated protein kinase signaling pathway but rather to the AKT–mammalian target of rapamycin–glycogen synthase kinase 3β signaling cascade.

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“…This mechanistic connection is demonstrated by the rescue of function and reduced injury seen after restoration of PI3K signaling. Thus, the authors demonstrated that PI3K-dependent but Akt-independent pathways are crucial for full cardioprotection and suggest a mechanism by which chronic Akt activation may become maladaptive (47). A possible explanation for the apparent controversial results of the literature could be the origin of Akt activation, since the models being considered are undoubtedly different, one being an exercise training model and the other represented by transgenic mice with exacerbated Akt activation.…”

Section: Exercise-induced Cardiac Hypertrophy Via At1 Receptormentioning

confidence: 99%

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

Fernandes

Soci

Oliveira

2011

Braz J Med Biol Res

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PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury

Cited by 218 publications

References 57 publications

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

C‐C Motif Chemokine Receptor 9 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

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