2018
DOI: 10.1161/circresaha.117.311147
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New Insights Into the Role of mTOR Signaling in the Cardiovascular System

Abstract: The mTOR (mechanistic target of rapamycin) is a master regulator of several crucial cellular processes, including protein synthesis, cellular growth, proliferation, autophagy, lysosomal function, and cell metabolism. mTOR interacts with specific adaptor proteins to form 2 multiprotein complexes, called mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). In the cardiovascular system, the mTOR pathway regulates both physiological and pathological processes in the heart. It is needed for embryonic cardiovascular… Show more

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Cited by 380 publications
(329 citation statements)
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References 164 publications
(233 reference statements)
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“…In line with our results, previous studies suggest that RhoA and ROCK mediate the activation of FAK, which associates with the regulatory p85 subunit of PI3K, activating it to mediate downstream activation of AKT in cultured neonatal cardiomyocytes (35,36). In addition, our results are consistent with the previously reported inverse relationship between autophagy and cardiac fibrosis during aging, attributable to elevated mTOR activity; such a decline of autophagy induces accumulation of misfolded proteins, dysfunctional organelles, and increased oxidative stress, which facilitate senescence in the heart and increase cardiac fibrosis and other abnormalities (30,31,(37)(38)(39). Because increased oxidative stress and accumulation of damaged proteins and organelles in the heart also occur in response to pathologic insults, including pressure overload, ischemic injury, and both genetic and metabolic cardiomyopathies in which partial genetic or pharmacological inhibition of mTOR signaling is beneficial (31), double ROCK deletion in the heart is anticipated to exert beneficial effects during cardiac stress through inhibiting mTOR activity and facilitating autophagy.…”
Section: Discussionsupporting
confidence: 91%
See 1 more Smart Citation
“…In line with our results, previous studies suggest that RhoA and ROCK mediate the activation of FAK, which associates with the regulatory p85 subunit of PI3K, activating it to mediate downstream activation of AKT in cultured neonatal cardiomyocytes (35,36). In addition, our results are consistent with the previously reported inverse relationship between autophagy and cardiac fibrosis during aging, attributable to elevated mTOR activity; such a decline of autophagy induces accumulation of misfolded proteins, dysfunctional organelles, and increased oxidative stress, which facilitate senescence in the heart and increase cardiac fibrosis and other abnormalities (30,31,(37)(38)(39). Because increased oxidative stress and accumulation of damaged proteins and organelles in the heart also occur in response to pathologic insults, including pressure overload, ischemic injury, and both genetic and metabolic cardiomyopathies in which partial genetic or pharmacological inhibition of mTOR signaling is beneficial (31), double ROCK deletion in the heart is anticipated to exert beneficial effects during cardiac stress through inhibiting mTOR activity and facilitating autophagy.…”
Section: Discussionsupporting
confidence: 91%
“…2F). Because the activation of the mTOR signaling pathway inhibits autophagy function (29)(30)(31), the reduced mTOR activity as indicated by reduced p-mTOR levels likely contributes to the increased LC3-II levels found in the double ROCK knockout hearts.…”
Section: Late Molecular Changes Associated With Inducible Cardiomyocymentioning
confidence: 99%
“…mTOR is the crucial signaling hub connecting cell growth and survival, and the activation of mTOR regulates lipid synthesis, mitochondrial function and glucose metabolism [26][27]. According to the observed effects of IL-22 on mitochondrial function and cell metabolism, we tested whether IL-22 controls the activity of mTOR signaling transduction.…”
Section: Il-22 Maintains Mitochondrial Function and Integrity Throughmentioning
confidence: 99%
“…mTOR, a serine-threonine kinase, is the master regulator of protein synthesis to drive anabolic growth and hypertrophy, and is critical for embryonic cardiac growth and post-natal development (180). Nonetheless, sustained alterations in cardiac metabolism can lead to prolonged activation of mTOR with adverse consequences (reviewed in Sciarretta et al (180)).…”
Section: Introductionmentioning
confidence: 99%
“…mTOR, a serine-threonine kinase, is the master regulator of protein synthesis to drive anabolic growth and hypertrophy, and is critical for embryonic cardiac growth and post-natal development (180). Nonetheless, sustained alterations in cardiac metabolism can lead to prolonged activation of mTOR with adverse consequences (reviewed in Sciarretta et al (180)). While unopposed stimulation of the LYNUS ( Ly sosomal Nu trient S ensing complex)-mTOR axis can provoke contractile dysfunction in cardiometabolic disease states (182, 198, 250), accumulating experimental evidence from our lab and others indicates that cyclic activation and inactivation of this pathway during periods of feeding and fasting may restore cellular homeostasis, in a manner that depends on intact autophagy and lysosomal function (72) (13, 119), Indeed, studies from C. elegans to humans support the notion that fasting strategies prolong lifespan, prevent life-threatening illnesses such as cancer, stimulate cellular regeneration and enhance the ability of organisms to endure subsequent stress (25, 39, 76, 88, 229, 240).…”
Section: Introductionmentioning
confidence: 99%