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 development and for maintaining cardiac homeostasis in postnatal life. Studies involving mTOR loss-of-function models revealed that mTORC1 activation is indispensable for the development of adaptive cardiac hypertrophy in response to mechanical overload. mTORC2 is also required for normal cardiac physiology and ensures cardiomyocyte survival in response to pressure overload. However, partial genetic or pharmacological inhibition of mTORC1 reduces cardiac remodeling and heart failure in response to pressure overload and chronic myocardial infarction. In addition, mTORC1 blockade reduces cardiac derangements induced by genetic and metabolic disorders and has been reported to extend life span in mice. These studies suggest that pharmacological targeting of mTOR may represent a therapeutic strategy to confer cardioprotection, although clinical evidence in support of this notion is still scarce. This review summarizes and discusses the new evidence on the pathophysiological role of mTOR signaling in the cardiovascular system.

Keywords: autophagy; cardiovascular diseases; heart; hypertrophy; mice.

Figure 1. Structure of mTOR complex 1 (mTORC1) and mTORC2

Schematic representation of the different subunits of mTORC1 and mTORC2, together with a description of their functions. Legend: DEPTOR, DEP domain-containing mTOR-interacting protein; mLST8, mammalian lethal with sec-13 protein 8; PRAS40, proline-rich Akt substrate 40; Protor 1/2, protein observed with rictor 1/2; Raptor, regulatory-associated protein of mammalian target of rapamycin (mTOR); rictor, rapamycin insensitive companion of mTOR; Tel1/2, Tel two interacting protein 1.

Figure 2. mTORC1 regulation of protein synthesis and cell metabolism

Schema representing the molecular mechanisms through which mTORC1 controls protein synthesis (a) and modulates cell metabolism (b). Legend: 40S, eukaryotic small ribosomal subunit; 4EB-P1, eukaryotic translation initiation factor 4E (eIF4E)-binding protein-1; eIF4B, eukaryotic translation initiation factor 4B; eIF4G, eukaryotic translation initiation factor 4G; EPRS, glutamylprolyl-tRNAsynthetase; HIF-1, hypoxia-inducible factor-1α; PDCD4, programmed cell death 4; S6K1, S6 kinase-1; SKAR, S6K1 Aly/REF-like substrate; SREBP1/2, sterol regulatory element-binding protein 1/2; YY1/PGC-1α, transcription factor yin-yang 1/peroxisome proliferator–activated receptor γ coactivator-1α transcriptional complex.

Figure 3. Main cellular functions and substrates of mTORC2

Schema representing the main cellular functions and substrates of mTORC2. Legend: Akt, protein kinase B; FoxO1/3, Forkhead box O1/3; PKC-α, protein kinase C-α; LATS, large tumor suppressor kinase 1; MST1, mammalian sterile 20- like kinase 1; RhoA, Ras homolog gene family, member A; SGK1, serum- and glucocorticoid-induced protein kinase-1; YAP, yes associated protein.

Figure 4. mTORC1 modulation of autophagy and lysosomal function

Schema representing the molecular mechanisms through which mTORC1 inhibits autophagy and lysosomal function. Legend: AMBRA1, (activating molecule in Beclin1-regulated autophagy; ATG, autophagy-related gene; FIP200, focal adhesion kinase family interacting protein of 200 kD; LC3, Light chain 3; ULK1/2, unc-51-like kinase 1/2; TFEB, transcription factor EB.

Figure 5. Schematic overview of the upstream signaling modulators of mTORC1 and mTORC2

Signaling network regulating mTORC1 and mTORC2 activity. Arrows indicate the effects of different conditions or cellular events on mTOR activity. Red arrows represent maladaptive input signals, whereas green arrows represent adaptive input signals. Legend: AMPK, adenosine monophosphate activated protein kinase; Akt, protein kinase B; CASTOR 1/2, cellular arginine sensor for mTORC1 1/2; ERK1/2, extracellular signal regulated kinase 1/2; GATOR 1/2, GAP activity towards Rags 1/2; GSK-3β, glycogen synthase kinase-3β; IKKβ, inhibitor of NF-κB kinase-β; PI3K, phosphoinositide 3 kinase; PRAS40, proline-rich Akt substrate 40; Rag, Ras-related GTPase; Raptor, regulatory-associated protein of mTOR; REDD1, regulated in development and DNA damage response 1; Rheb, Ras homolog enriched in brain; TSC1/2, tuberous sclerosis protein 1/2.