The functions of mTOR in ischemic diseases

Hwang, Seo-Kyoung; Kim, Hyung-Hwan

doi:10.5483/bmbrep.2011.44.8.506

Cited by 53 publications

(40 citation statements)

References 55 publications

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“…In addition to its effects on Bcl-2 and mitochondrial apoptosis, p38 also affects a wide spectrum of other cell signaling molecules including mTOR [10,[35][36][37] and inflammatory pathways [10,36,38]. Our data suggest that mTOR does not play a role in UCN2-induced protection as UCN2 did not affect mTOR expression and phosphorylation.…”

Section: Discussioncontrasting

confidence: 52%

Urocortin-2 suppression of p38-MAPK signaling as an additional mechanism for ischemic cardioprotection

et al. 2014

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Urocortin-2 (UCN2) is cardioprotective in ischemia/reperfusion injury (I/R) through short-lived activation of ERK1/2. Key factors involved in I/R, e.g. apoptosis, mitochondrial damage, p38 kinase, and Bcl-2 family, have not been well-investigated in UCN2-induced cardioprotection. We assessed the role of p38-MAPK in anti-apoptotic Bcl-2 signaling and mitochondrial stabilization as a putative mechanisms in UCN2-induced cardioprotection. Isolated hearts from adult Sprague-Dawley rats and cultured H9c2 cells were subjected to I/R protocols with or without 10 nM UCN2 treatment. The effect of a specific p38 inhibitor SB202190 was tested in H9c2 cells. Cardiac function, LDH release, and mitochondrial membrane potential (MMP) were used to assess the degree of myocardial injury in hearts and H9c2 cells. Post-perfusion, hearts were collected for Western blot analyses or mitochondria/cytosol isolation to analyze p38 activation and Bcl-2 family members. UCN2 treatment improved rate-pressure product (58 ± 5 vs. 31 ± 4 % of Baseline; P < 0.05) and decreased LDH release (20 ± 9 vs. 90 ± 40 mU/ml LDH, P < 0.01) at the end of 60 min reperfusion. UCN2 reduced phospho-p38 levels and Bax activation. UCN2 increased the expression of Bcl-2 and inhibited the accumulation of p-Bim. With additional experiments, it was confirmed that UCN2 increases the phosphorylation of ERK1/2 in the early phase of UCN2 treatment and increases the overshot recovery of ERK1/2 phosphorylation during reperfusion. UCN2 and SB202190 partially prevented the loss of MMP induced by I/R. However, combined treatment with UCN2 and SB202190 did not provide additive benefit. UCN2 is cardioprotective in I/R in association with reduced phosphorylation of p38 together with the increased ERK1/2 activation and increased Bcl-2 family member pro-survival signaling. These changes may stabilize cardiac mitochondria, similar to p38 inhibitors, as part of a pro-survival mechanism during I/R.

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Section: Discussioncontrasting

confidence: 52%

Urocortin-2 suppression of p38-MAPK signaling as an additional mechanism for ischemic cardioprotection

et al. 2014

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“…As an immune-suppressive and anti-proliferative agent, RPM therapeutic effects and functional mechanisms in the pathogenesis of IRI remain controversial (1, 4, 13). Our results showed that RPM pre-treatment was able to protect livers from IRI in the presence of undiminished inflammatory immune activation by enhancing both hepatocyte autophagy, as well as the activation of mTORC2-Akt signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Protection of Livers From Ischemia and Reperfusion Injury Is Dependent on Both Autophagy Induction and Mammalian Target of Rapamycin Complex 2-Akt Activation

Zhu

Shi

et al. 2015

Transplantation

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Background Although Rapamycin (RPM) have been studied extensively in ischemia models, its functional mechanisms remains to be defined. Methods We determined how RPM impacted the pathogenesis of ischemia reperfusion injury (IRI) in a murine liver partial warm ischemia model, with emphasis on its regulation of hepatocyte death. Results RPM protected livers from IRI in the presence of fully developed liver inflammatory immune response. RPM enhanced liver autophagy induction at the reperfusion stage. Dual mTOR1/2 inhibitor Torin 1, despite its ability to induced autophagy, failed to protect livers from IRI. The treatment with RPM, but not Torin 1, resulted in the enhanced activation of the mTORC2-Akt signaling pathway activation in livers post reperfusion. Inactivation of Akt by Triciribine abolished liver protective effect of RPM. The differential cytoprotective effect of RPM and Torin 1 was confirmed in vitro in hepatocyte cultures. RPM, but not Trin 1, protected hepatocytes from stress and TNF-α induced cell death; and inhibition of either autophagy by chloroquine or Akt by Triciribine abolished RPM-mediated cytoprotection. Conclusion RPM protected livers from IRI via both autophagy and mTORC2-Akt activation mechanisms.

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“…The mTOR pathway has multiple roles in cardiac adaptability by controlling protein turnover through targets of rapamycin 38,39 , and modifies inflammatory response through regulation of immunoproteasomal degradation under hemodynamic stress. 31 We hypothesize that the proteomic enrichment of the mTOR pathway in the aged Emilin1−/− AV suggests that mTOR signaling may regulate an immune mechanism that modifies inflammatory processes and ultimately contributes to the progression of AV disease.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease

et al. 2017

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Aortic valve (AV) disease involves stiffening of the AV cusp with progression characterized by inflammation, fibrosis, and calcification. Here, we examine the relationship between biomechanical valve function and proteomic changes before and after the development of AV pathology in the Emilin1−/− mouse model of latent AV disease. Biomechanical studies were performed to quantify tissue stiffness at the macro (micropipette) and micro (atomic force microscopy (AFM)) levels. Micropipette studies showed that the Emilin1−/− AV annulus and cusp regions demonstrated increased stiffness only after the onset of AV disease. AFM studies showed that the Emilin1−/− cusp stiffens before the onset of AV disease and worsens with the onset of disease. Proteomes from AV cusps were investigated to identify protein functions, pathways, and interaction network alterations that occur with age- and genotype-related valve stiffening. Protein alterations due to Emilin1 deficiency, including changes in pathways and functions, preceded biomechanical aberrations, resulting in marked depletion of extracellular matrix (ECM) proteins interacting with TGFB1, including latent transforming growth factor beta 3 (LTBP3), fibulin 5 (FBLN5), and cartilage intermediate layer protein 1 (CILP1). This study identifies proteomic dysregulation is associated with biomechanical dysfunction as early pathogenic processes in the Emilin1−/− model of AV disease.

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The functions of mTOR in ischemic diseases

Cited by 53 publications

References 55 publications

Urocortin-2 suppression of p38-MAPK signaling as an additional mechanism for ischemic cardioprotection

Urocortin-2 suppression of p38-MAPK signaling as an additional mechanism for ischemic cardioprotection

Rapamycin Protection of Livers From Ischemia and Reperfusion Injury Is Dependent on Both Autophagy Induction and Mammalian Target of Rapamycin Complex 2-Akt Activation

Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease

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