Nerve growth factor-induced Akt/mTOR activation protects the ischemic heart via restoring autophagic flux and attenuating ubiquitinated protein accumulation

Wang, Zhouguang; Li, Hao; Huang, Yan; Li, Rui; Wang, Xiaofan; Liu, Yu; Xue-Qiang, Guang; Li, Lei; Zhang, Hongyu; Zhao, Ying‐Zheng; Zhang, Chunxiang; Li, Xiaokun; Wu, Rongzhou; Chu, Maoping; Xiao, Jian

doi:10.18632/oncotarget.14284

Cited by 32 publications

(28 citation statements)

References 46 publications

(47 reference statements)

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“…Evidence also indicates that activation of PI3K/Akt/mTOR pathway negatively regulated autophagy characterized by downregulation of autophagic marker LC3 [14, 15]. For example, nerve growth factor protected ischemic heart by inhibition of autophagy related proteins via activating PI3K/Akt/mTOR pathway [16]. Conversely, inhibition of mTOR signaling with rapamycin was found to induce autophagy.…”

Section: Introductionmentioning

confidence: 99%

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

Hang

Zhao

et al. 2018

Cell Physiol Biochem

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Backgroud/Aims: Growing evidence suggests that both cardiomyocyte apoptosis and excessive autophagy exacerbates cardiac dysfunction during myocardial ischemia-reperfusion (IR). As a precursor of acetylcholine, choline has been found to protect the heart by repressing ischemic cardiomyocyte apoptosis. However, the relationship between choline and cardiomyocyte autophagy is unclear. The present study aimed to investigate whether autophagy was involved in the cardioprotection of choline during IR. Methods: Rats were subjected to 30 min reversible ischemia by ligation of left anterior descending coronary artery followed by reperfusion for 2 h. Choline (5 mg/kg, i.v.) alone or along with rapamycin (5 mg/ kg, i.p.) were injected 30 min before ischemia. Transmission electron microscopy, hematoxylin and eosin (HE) and TUNEL staining were conducted to evaluate the effect of choline on cardiac apoptosis and autophagy. Protein levels of autophagic markers including LC3, beclin-1 and p62 as well as Akt and mammalian target of rapamycin (mTOR) were examined by Western blotting. Results: Myocardial IR-induced cardiac apoptosis and accumulation of autophagosomes was attenuated by choline. Choline treatment significantly ameliorated myocardial IR-induced autophagic activity characterized by repression of beclin-1 over-activation, the reduction of autophagosomes, the LC3-II/LC3-I ratio, and p62 protein abundance. In addition, IR-induced downregulation of p-Akt/mTOR cascade was increased by choline. However, the above functions of choline were abolished by rapamycin. Conclusion: These findings suggest that choline plays a protective role against myocardial IR injury by inhibiting excessive autophagy, which might be associated with the activation of Akt/mTOR pathway. This study provides new mechanistic understanding of cardioprotective effect of choline and suggests novel potential therapeutic targets for cardiac IR injury.

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Section: Introductionmentioning

confidence: 99%

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

Hang

Zhao

et al. 2018

Cell Physiol Biochem

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“…The pAMPK/AMPK ratio was significantly reduced, indicating that AMPK activity was suppressed. The activity of mTOR, an essential negative regulator of autophagy along with Akt ( Ejaz et al, 2016 ; Wang et al, 2017 ) and also related to AMPK on direct modulation of Ulk1, the autophagy initiating kinase ( Kim et al, 2011 ), was analyzed by changes in the ratio of pmTOR/mTOR. The pmTOR/mTOR ratio was significantly enhanced, showing that mTOR was activated.…”

Section: Resultsmentioning

confidence: 99%

Cordyceps militaris improves the survival of Dahl salt-sensitive hypertensive rats possibly via influences of mitochondria and autophagy functions

Takakura

Ito

Sonoda

et al. 2017

Heliyon

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The genus Cordyceps and its specific ingredient, cordycepin, have attracted much attention for multiple health benefits and expectations for lifespan extension. We analyzed whether Cordyceps militaris (CM), which contains large amounts of cordycepin, can extend the survival of Dahl salt-sensitive rats, whose survival was reduced to ∼3 months via a high-salt diet. The survival of these life-shortened rats was extended significantly when supplemented with CM, possibly due to a minimization of the effects of stroke. Next, we analyzed the effect of CM on hypertension-sensitive organs, the central nervous systems (CNS), heart, kidney and liver of these rats. We attempted to ascertain how the organs were improved by CM, and we paid particular attention to mitochondria and autophagy functions. The following results were from CM-treated rats in comparison with control rats. Microscopically, CNS neurons, cardiomyocytes, glomerular podocytes, renal epithelial cells, and hepatocytes all were improved. However, immunoblot and immunohistochemical analysis showed that the expressions of mitochondria-related proteins, ATP synthase β subunit, SIRT3 and SOD2, and autophagy-related proteins, LC3-II/LC3-I ratio and cathepsin D all were reduced significantly in the CNS neurons, but increased significantly in the cells of the other three organs, although p62 was decreased in its expression in all the organs tested. Activity of Akt and mTOR was enhanced but that of AMPK was reduced in the CNS, while such kinase activity was completely the opposite in the other organs. Together, the influence of CM may differ between mitochondria and autophagy functioned between the two organ groups, as mitochondria and autophagy seemed to be repressed and promoted, respectively, in the CNS, while both mitochondria and autophagy were activated in the others. This could possibly be related to the steady or improved cellular activity in both the organs, which might result in the life extension of these rats.

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“…2016; Wang et al. 2017), we also investigated whether this cellular self‐degradation process limits apoptosis during RSV infection by measuring expression of the early marker beclin‐1. This mammalian homolog of yeast Atg6/Vps30 is at the heart of a regulatory complex for the class III PI3K/hVps34, and its activity is essential during autophagosome formation (Liang et al.…”

Section: Discussionmentioning

confidence: 99%

“…2016; Wang et al. 2017). This evolutionarily conserved process of cellular self‐degradation allows the selective digestion of damaged or unneeded cytosolic substructures into amino acids and fatty acids that can be recycled for macromolecular synthesis and energy production essential for cell survival and stress adaptation.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticles increase human bronchial epithelial cell susceptibility to respiratory syncytial virus infection via nerve growth factor-induced autophagy

et al. 2017

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Cytotoxic and neuroinflammatory effects of TiO2 nanoparticles (TiO2‐NP) in human airways are mediated by nerve growth factor (NGF), which is also implicated in the pathophysiology of respiratory syncytial virus (RSV) infection. We tested the hypothesis that exposure to TiO2‐NP results in increased susceptibility to RSV infection and exacerbation of airway inflammation via NGF‐mediated induction of autophagy in lower respiratory tract cells. Human primary bronchial epithelial cells were exposed to TiO2‐NP for 24 h prior to infection with recombinant red RSV (rrRSV). Expression of NGF and its TrkA and p75NTR receptors was measured by real‐time PCR and fluorescence‐activated cell sorting (FACS). Autophagy was assessed by beclin‐1 expression analysis. Cell death was studied by FACS after annexin V/propidium iodide staining. rrRSV infection efficiency more than doubled in human bronchial cells pre‐exposed to TiO2‐NP compared to controls. NGF and its TrkA receptor were upregulated in RSV‐infected bronchial cells pre‐exposed to TiO2‐NP compared to controls exposed to either rrRSV or TiO2‐NP alone. Silencing NGF gene expression with siRNA significantly inhibited rrRSV infection. rrRSV‐infected cells pre‐exposed to TiO2‐NP also showed increase in necrotic cell death and reduction in apoptosis, together with 4.3‐fold increase in expression of the early autophagosomal gene beclin‐1. Pharmacological inhibition of beclin‐1 by wortmannin resulted in increased apoptotic rate along with lower viral load. This study shows that TiO2‐NP exposure enhances the infectivity of RSV in human bronchial epithelial cells by upregulating the NGF/TrkA axis. The mechanism of this interaction involves induction of autophagy promoting viral replication and necrotic cell death.

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Nerve growth factor-induced Akt/mTOR activation protects the ischemic heart via restoring autophagic flux and attenuating ubiquitinated protein accumulation

Cited by 32 publications

References 46 publications

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

Cordyceps militaris improves the survival of Dahl salt-sensitive hypertensive rats possibly via influences of mitochondria and autophagy functions

Nanoparticles increase human bronchial epithelial cell susceptibility to respiratory syncytial virus infection via nerve growth factor-induced autophagy

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