mTOR and vascular remodeling in lung diseases: current challenges and therapeutic prospects

Abstract

Mammalian target of rapamycin (mTOR) is a major regulator of cellular metabolism, proliferation, and survival that is implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, and cancer. Emerging evidence suggests a potential critical role of mTOR signaling in pulmonary vascular remodeling. Remodeling of small pulmonary arteries due to increased proliferation, resistance to apoptosis, and altered metabolism of cells forming the pulmonary vascular wall is a key currently irreversible pathological feature of pulmonary hypertension, a progressive pulmonary vascular disorder with high morbidity and mortality. In addition to rare familial and idiopathic forms, pulmonary hypertension is also a life-threatening complication of several lung diseases associated with hypoxia. This review aims to summarize our current knowledge and recent advances in understanding the role of the mTOR pathway in pulmonary vascular remodeling, with a specific focus on the hypoxia component, a confirmed shared trigger of pulmonary hypertension in lung diseases. We also discuss the emerging role of mTOR as a promising therapeutic target and mTOR inhibitors as potential pharmacological approaches to treat pulmonary vascular remodeling in pulmonary hypertension.

Figure 1.

The mTOR signaling pathway. mTORC1 promotes mRNA translation, protein and lipid synthesis, and cell proliferation; up-regulates glycolysis; and inhibits autophagy by integrating growth factor signals, nutrient availability, energy levels, and various stress factors, including hypoxia. Growth factors activate mTORC1 via up-regulating PI3K/PDK1/Thr308-Akt and Ras/ERK1/2 signaling pathways. Akt and ERK, in turn, phosphorylate TSC2, thus inhibiting TSC1/TSC2 GAP activity toward Rheb. In contrast, energy stress, including hypoxia, activates AMPK and Redd1, which promote the assembly and activation of TSC1/TSC2, leading to mTORC1 inhibition. Amino acids activate mTORC1 via Rag GTPase-induced translocation to lysosomes, which enables mTORC1 to interact with Rheb. Activated mTORC1 phosphorylates S6K1 and 4E-BP1, leading to activation of ribosomal protein S6 and eIF2E, mRNA translation, and protein synthesis; stimulates lipid synthesis via activation of SREBP1, PPAR-γ, and C/EBP-α; promotes glycolysis potentially via expression of HIF1α; and inhibits autophagy directly via phosphorylation of ULK1-Atg13-FIP200 complex or indirectly via S6K. mTORC2 is activated by growth factors and insulin in a PI3K-dependent manner, and, in turn, activates Akt by phosphorylation at S473, SGK1, PKCα, and Rho GTPases (39, 40). Akt and SGK1 phosphorylate and inhibit FoxO1 and FoxO3a transcription factors that regulate stress resistance, metabolism, cell-cycle arrest, and apoptosis. mTORC2 also stimulates HIF1α expression and glycolysis by unknown mechanisms and modulates cytoskeletal organization via PKCα, paxillin, and small Rho GTPases.

Figure 2.

Schematic representation of the roles of mTORC1 and mTORC2 in pulmonary vascular remodeling. A) Increased levels of growth factors and vasoconstrictors and chronic hypoxia activate mTORC1, which, in turn, promotes cell growth and proliferation via S6K1-S6 signaling pathway. mTORC1 may also stimulate proliferation via inducing Ca²⁺ release (shown only for PAVSMCs). B) Growth factors, vasoconstrictors, and chronic hypoxia activate mTORC2, which stimulates PAVSMC proliferation and resistance to apoptosis by unknown mechanisms.

Figure 3.

Potential effects of therapeutic inhibition of mTOR signaling on pulmonary vascular remodeling. A) mTOR signaling in the absence of inhibitors. B, C) Therapeutic inhibition of mTOR by prolonged rapamycin treatment of cells with rapamycin (rapa)-resistant (B) and rapamycin-sensitive mTORC2 (C). D) Therapeutic inhibition of mTOR by mTOR kinase inhibitors. E) Potential effects of prolonged rapamycin treatment and mTOR kinase inhibitors on existing pulmonary vascular remodeling.