Rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium

Harston, Rebecca K.; McKillop, John; Moschella, Phillip; Laer, An O. Van; Quinones, Lakeya; Baicu, Catalin F.; Balasubramanian, Sundaravadivel; Zile, Michael R.; Kuppuswamy, Dhandapani

doi:10.1152/ajpheart.00545.2010

Cited by 34 publications

(41 citation statements)

References 42 publications

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“…Beneficial cardiac remodeling in rapamycintreated (clinically used derivative) cardiac transplant patients with improved LVH and cardiac func tion was also reported. 18 Moreover, deletion of the defin ing mTORC1 protein, raptor, in male mice 19 or rapamycin intervention in a rat pulmonarybanding model 20 have been shown to activate mTORC2, most probably attributable to a release of a negative feedback inhibition as occurs in can cer. 21 However, these studies did not investigate mTORC2 in female mice or female patients.…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific mTOR Signaling Determines Sexual Dimorphism in Myocardial Adaptation in Normotensive DOCA-Salt Model

et al. 2013

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Abstract-The deoxycorticosterone acetate (DOCA)salt mouse model exhibits adverse cardiac remodeling in male mice and cardiac protection in female mice, even when blood pressure is normalized. We hypothesized that intact mammalian target of rapamycin (mTOR) signaling is necessary for cardiac protection in females. We first tested sex differences and intracellular signaling after mTOR targeting with rapamycin in wildtype mice. Radiotelemetric blood pressure was maintained at normal for 6 weeks. Rapamycin significantly reduced left ventricular hypertrophy, preserved ejection fraction, inhibited fibrosis, and maintained capillary structure in male mice. Decreased mTORC1 and increased mTORC2 activity were detected in rapamycintreated male mice compared with vehicle controls. In contrast, female mice developed dilative left ventricular hypertrophy, cardiac fibrosis, and capillary loss similar to DOCAsalt females lacking the estrogen receptor β (ERβ −/− ) that we described earlier. Because rapamycin downregulated ERβ in female mice, we next studied ERβ −/− normotensive DOCA salt females. Vehicletreated wildtype females maintained their high constitutive mTORC1 and mTORC2 in response to DOCAsalt. In contrast to males, both mTORCs were decreased by rapamycin, in particular mTORC2 by 60%. ERβ −/− DOCAsalt females showed similar mTORC1 and mTORC2 response patterns. We suggest that ERβdependent regulation involves sexspecific use of mTOR signaling branches. Maintenance of both mTORC1 and mTORC2 signaling seems to be essential for adaptive cardiac remodeling in females and supports a rationale for sexspecific therapeutic strategies in left

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Section: Discussionmentioning

confidence: 99%

Sex-Specific mTOR Signaling Determines Sexual Dimorphism in Myocardial Adaptation in Normotensive DOCA-Salt Model

et al. 2013

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“…Considering that proteasome inhibitor MG132 further increased polyubiquitinated proteins ratio, rasfonin may function as an inducer in the process of ubiquitination. Thus, similar to another autophagy inducer rapamycin (Harston et al 2011), rasfonin can activate both UPS and autophagic pathway in ACHN cells. However, the underlying mechanism needs to be further revealed, and our next part of work will focus on it.…”

Section: Discussionmentioning

confidence: 79%

Proteasome inhibition attenuates rasfonin-induced autophagy concurring with the upregulation of caspase-dependent apoptosis

Yan

Che²,

Jiang

2016

Mycology

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Two major protein quality control mechanisms exist in eukaryotic cells, the ubiquitin-proteasome system (UPS) and the autophagy–lysosome system. Generally, the inhibition of UPS is believed to enhance autophagic pathway; nevertheless, the crosstalk between these two degradation systems may be much more complicated. Rasfonin, a 2-pyrone derivative of fungal secondary metabolites, is demonstrated to have the antitumor effect and can function as an autophagy inducer. Here, we reported that rasfonin activated multiple cell death pathways, including caspase-dependent apoptosis. Using electroscopy and microscopy, we observed rasfonin increased the formation of autophagosome. In immunoblotting assay, rasfonin enhanced autophagic flux concomitant with the upregulation of ubiquitination. MG132, an inhibitor of proteasome, attenuated rasfonin-dependent autophagy, whereas its presentation stimulated rasfonin-induced cleavage of poly (ADP-ribose) polymerase, a marker of caspase-dependent apoptosis. Together, we demonstrated that rasfonin induced the activation of both UPS and autophagic pathway, and the inhibition of UPS attenuated rasfonin-induced autophagy and enhanced the cytotoxicity of rasonin by upregulation of caspase-dependent apoptosis.

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“…31,32 Acute treatment with a pharmacological antagonist rapamycin specifically blocks the activity of mTORC1, whereas torin1 inhibits both mTORC1 and mTORC2. Our study shows that blocking mTORC1 with acute rapamycin treatment results in an increased mTORC2 activity in both PO myocardium in vivo and in agoniststimulated adult CM in vitro 33 and that distinct PKC isoforms are involved in the signaling mechanisms by both these complexes. 26,34 Several studies implicate a link between the delta isoform of protein kinase C (PKC d ) and mTOR, 35,36 and our earlier work has shown that it plays an upstream role in mTOR phosphorylation in hypertrophic agonist-stimulated adult CM.…”

Section: Introductionmentioning

confidence: 64%

“…Pretreatment of cells with torin1 blocks both mTOR complexes and was found to augment PE-stimulated CTGF expression. However, pretreatment of cells with rapamycin, which was shown to affect mTORC1 but promoted mTORC2, 33 did not affect PEstimulated CTGF-gene expression. In this context, chronic in vivo treatment of rats for 3 weeks with everolimus, a derivative of rapamycin, was found to augment CTGF expression.…”

Section: Discussionmentioning

confidence: 86%

mTOR Complexes Repress Hypertrophic Agonist–Stimulated Expression of Connective Tissue Growth Factor in Adult Cardiac Muscle Cells

Sundararaj

Pleasant

Moschella

et al. 2016

Journal of Cardiovascular Pharmacology

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Connective tissue growth factor (CTGF) is a fibrogenic cytokine that promotes fibrosis in various organs. In the heart, both cardiomyocytes (CM) and cardiac fibroblasts have been reported as a source of CTGF expression, aiding cardiac fibrosis. Although the mammalian target of rapamycin (mTOR) forms 2 distinct complexes, mTORC1 and mTORC2, and plays a central role in integrating biochemical signals for protein synthesis and cellular homeostasis, we explored its role in CTGF expression in adult feline CM. CM were stimulated with 10 μM phenylephrine (PE), 200 nM angiotensin (Ang), or 100 nM insulin for 24 hours. PE and Ang, but not insulin, caused an increase in CTGF mRNA expression with the highest expression observed with PE. Inhibition of mTOR with torin1 but not rapamycin significantly enhanced PE-stimulated CTGF expression. Furthermore, silencing of raptor and rictor using shRNA adenoviral vectors to suppress mTORC1 and mTORC2, respectively, or blocking phosphatidylinositol 3-kinase (PI3K) signaling with LY294002 (LY) or Akt signaling by dominant-negative Akt expression caused a substantial increase in PE-stimulated CTGF expression as measured by both mRNA and secreted protein levels. However, studies with dominant-negative delta isoform of protein kinase C demonstrate that delta isoform of protein kinase C is required for both agonist-induced CTGF expression and mTORC2/Akt-mediated CTGF suppression. Finally, PE-stimulated CTGF expression was accompanied with a corresponding increase in Smad3 phosphorylation and pretreatment of cells with SIS3, a Smad3 specific inhibitor, partially blocked the PE-stimulated CTGF expression. Therefore, a PI3K/mTOR/Akt axis plays a suppressive role on agonist-stimulated CTGF expression where the loss of this mechanism could be a contributing factor for the onset of cardiac fibrosis in the hypertrophying myocardium.

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Rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium

Cited by 34 publications

References 42 publications

Sex-Specific mTOR Signaling Determines Sexual Dimorphism in Myocardial Adaptation in Normotensive DOCA-Salt Model

Sex-Specific mTOR Signaling Determines Sexual Dimorphism in Myocardial Adaptation in Normotensive DOCA-Salt Model

Proteasome inhibition attenuates rasfonin-induced autophagy concurring with the upregulation of caspase-dependent apoptosis

mTOR Complexes Repress Hypertrophic Agonist–Stimulated Expression of Connective Tissue Growth Factor in Adult Cardiac Muscle Cells

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