mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy

Taneike, Manabu; Nishida, Keiya; Omiya, Shigemiki; Zarrinpashneh, Elham; Misaka, Tomofumi; Kitazume-Taneike, Rika; Austin, Ruth; Takaoka, Minoru; Yamaguchi, Osamu; Gambello, Michael J.; Shah, Ajay M.; Otsu, Kinya

doi:10.1371/journal.pone.0152628

Cited by 51 publications

(55 citation statements)

References 57 publications

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“…In yeast and mammalian cells, the Ras and mTOR pathways are two well-known signaling cascades that are sensitive to nutrient status, cell growth and differentiation, and are negatively regulated during programmed cell death (34). The phosphoinositide 3-kinase/Akt/mTOR pathway exists in several types of cancer and may be activated by the loss of tumor suppressor phosphatase and tensin homolog (PTEN) function (35).…”

Section: Discussionmentioning

confidence: 99%

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

et al. 2016

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Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

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Section: Discussionmentioning

confidence: 99%

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

et al. 2016

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“…CFs were incubated with 3AB (10 μM, 24 hours) or ABT-888 (10 μM, 24 hours) followed by incubation with TGF-β1 (10 ng/mL for 24 hours). [11][12][13][14][15][16][17][18][19][20][21] It is mainly due to the effect of mTOR on collagen expression, Smad3, p53/JNK-mediated F I G U R E 6 Involvement of mTOR in PARP1-mediated cardiac fibrosis in vitro. B and G, The protein levels of PARP1 and mTOR were determined by Western blot analysis.…”

Section: Discussionmentioning

confidence: 99%

“…8 In particular, activated mTORC1 positively regulates protein synthesis by phosphorylating its downstream substrates, such as p70 ribosomal S6 kinase 1 (S6K1), eukaryotic initiation factor 4E-binding protein 1 (4EBP, eIF4Ebinding protein 1), and UNC51like kinase 1 (ULK1). [11][12][13][14][15][16][17][18][19][20][21] It is mainly due to the effect of mTOR on cardiac collagen expression, Smad3, p53/JNK-mediated apoptosis, autophagy, and inflammatory response. [11][12][13][14][15][16][17][18][19][20][21] It is mainly due to the effect of mTOR on cardiac collagen expression, Smad3, p53/JNK-mediated apoptosis, autophagy, and inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

“…10 It is well documented that mTOR signaling is associated with many cardiac diseases accompanied by cardiac fibrosis, including cardiac hypertrophy, dysfunction, dilated cardiomyopathy, and ischemia-reperfusion injury. 12,17,19,21 Poly(ADP-ribose) polymerase 1 (PARP1), the founding subtype of the PARPs enzyme family, attaches the polymers of ADP-ribose (PAR) to target proteins and consumes the cellular NAD pool. 12,17,19,21 Poly(ADP-ribose) polymerase 1 (PARP1), the founding subtype of the PARPs enzyme family, attaches the polymers of ADP-ribose (PAR) to target proteins and consumes the cellular NAD pool.…”

Section: Introductionmentioning

confidence: 99%

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Poly(ADP‐ribose) polymerase 1 induces cardiac fibrosis by mediating mammalian target of rapamycin activity

Sun

Zheng

et al. 2019

J of Cellular Biochemistry

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Cardiac fibrosis is involved in nearly all forms of heart diseases, and is characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts (CFs). We and others have reported the possibility of poly(ADP-ribose) polymerase 1 (PARP1), the founding subtype of the PARPs enzyme family, as a novel therapeutic target of heart diseases. The cardiac fibrotic induction of mTOR (mammalian target of rapamycin) is mainly due to collagen expression, Smad3 and p53/JNK-mediated apoptosis. However, the possible link between PARP1 and mTOR in the progression of cardiac fibrosis remains unclear. In this study, PARP1 protein expression, and the activity of mTOR and its three target substrates (S6K1, 4E-BP and ULK1) were augmented; meanwhile, the NAD content was significantly reduced in the process of cardiac fibrosis in vivo and in vitro. SD rats were intraperitoneally injected with 3AB (20 mg/kg/d, a well-established PARP1 inhibitor) or rapamycin (Rapa, 1 mg/kg/d, used for mTOR inhibition) 7 days after AAC (abdominal aortic constriction) surgery for 6 weeks. Pre-treatment of 3AB or Rapa both relieved AAC-caused cardiac fibrosis and heart dysfunction. Overexpression of PARP1 with adenovirus carrying PARP1 gene (Ad-PARP1) specifically transduced into the hearts via intramyocardial multi-point injection caused similar myocardial damage. In CFs, pre-incubation with PARP1 or mTOR inhibitors all blocked TGF-β1-induced cardiac fibrosis. PARP1 overexpression evoked cardiac fibrosis, which could be antagonized by mTOR inhibitors or NAD supplementation in CFs. These results provide novel and compelling evidence that PARP1 exacerbated cardiac fibrosis, which was partially attributed to NAD-dependent activation of mTOR. This article is protected by copyright. All rights reserved.

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“…3 We recently reported that autophagy via the tuberous sclerosis complex 2 (TSC2)-mechanistic or mammalian target of rapamycin complex 1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart using cardiac-specific TSC2-deficient mice. 43 Furthermore, mechanical unloading of the failing human heart by left ventricular assist device support (with a mean duration of 214 days) decreased markers of autophagy. 44 These findings suggest that autophagy is an adaptive mechanism in the failing heart.…”

Section: Sterile Inflammation and The Innate Immunementioning

confidence: 99%

Sterile Inflammation and Degradation Systems in Heart Failure

Nishida

Otsu

2017

Circ J

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In most patients with chronic heart failure (HF), levels of circulating cytokines are elevated and the elevated cytokine levels correlate with the severity of HF and prognosis. Various stresses induce subcellular component abnormalities, such as mitochondrial damage. Damaged mitochondria induce accumulation of reactive oxygen species and apoptogenic proteins, and subcellular inflammation. The vicious cycle of subcellular component abnormalities, inflammatory cell infiltration and neurohumoral activation induces cardiomyocyte injury and death, and cardiac fibrosis, resulting in cardiac dysfunction and HF. Quality control mechanisms at both the protein and organelle levels, such as elimination of apoptogenic proteins and damaged mitochondria, maintain cellular homeostasis. An imbalance between protein synthesis and degradation is likely to result in cellular dysfunction and disease. Three major protein degradation systems have been identified, namely the cysteine protease system, autophagy, and the ubiquitin proteasome system. Autophagy was initially believed to be a non-selective process. However, recent studies have described the process of selective mitochondrial autophagy, known as mitophagy. Elimination of damaged mitochondria by autophagy is important for maintenance of cellular homeostasis. DNA and RNA degradation systems also play a critical role in regulating inflammation and maintaining cellular homeostasis mediated by damaged DNA clearance and post-transcriptional regulation, respectively. This review discusses some recent advances in understanding the role of sterile inflammation and degradation systems in HF.

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mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy

Cited by 51 publications

References 57 publications

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

Poly(ADP‐ribose) polymerase 1 induces cardiac fibrosis by mediating mammalian target of rapamycin activity

Sterile Inflammation and Degradation Systems in Heart Failure

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