Abstract
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease without a cure. The exact pathogenic mechanisms of PAH are complex and poorly understood, yet a number of abnormally expressed genes and regulatory pathways contribute to sustained vasoconstriction and vascular remodeling of the distal pulmonary arteries. Mammalian target of rapamycin (mTOR) is one of the major signaling pathways implicated in regulating cell proliferation, migration, differentiation, and protein synthesis. Here we will describe the canonical mTOR pathway, structural and functional differences between mTOR complexes 1 and 2, as well as the crosstalk with other important signaling cascades in the development of PAH. The pathogenic role of mTOR in pulmonary vascular remodeling and sustained vasoconstriction due to its contribution to proliferation, migration, phenotypic transition, and gene regulation in pulmonary artery smooth muscle and endothelial cells will be discussed. Despite the progress in our elucidation of the etiology and pathogenesis of PAH over the two last decades, there is a lack of effective therapeutic agents to treat PAH patients representing a significant unmet clinical need. In this review, we will explore the possibility and therapeutic potential to use inhibitors of mTOR signaling cascade to treat PAH.
Highlights
Identified potential PDK2 kinases, i.e., DNA-dependent protein kinase (DNAPK) and Mammalian target of rapamycin (mTOR), are considered as Class IV PI3Ks. mTOR serves as a core component of two multi-protein distinct complexes: mTOR complex 1 that is highly sensitive to rapamycin, insulin, and growth factors, and mTOR complex 2 that is mostly insensitive to rapamycin
Published data demonstrate that mTOR is essential for pulmonary vascular remodeling and occlusive intimal lesions, which suggests mTORC1/2 complexes, Raptor and Rictor, may both contribute to the development and progression of pulmonary arterial hypertension (PAH)
Targeting the pathway using specific inhibitors for PI3K, AKT, mTOR, Raptor, or Rictor is considered as a good therapeutic strategy to develop novel and specific treatment for PAH
Summary
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease in which functional and structural changes in the pulmonary vasculature lead to the increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) [1,2]. Identified potential PDK2 kinases, i.e., DNA-dependent protein kinase (DNAPK) and mTOR, are considered as Class IV PI3Ks. mTOR serves as a core component of two multi-protein distinct complexes: mTOR complex 1 (mTORC1) that is highly sensitive to rapamycin, insulin, and growth factors, and mTOR complex 2 (mTORC2) that is mostly insensitive to rapamycin In both complexes, mTOR acts as serine/threonine protein kinase involved in the regulation of cell proliferation, survival, transcription, and protein synthesis, while in mTORC2, it functions as tyrosine protein kinase, which promotes activation of insulin receptors and controls the actin cytoskeleton. The stress and hypoxia response genes adenosine monophosphate-activated protein kinase (AMPK) and Redd (DNA damage response 1, known as RTP801/Dig2/DDIT4) can promote assembly of TSC1/TSC2 resulting in suppressive effect on mTORC1 pathway. The activity of AKT-T308 phosphorylation alone may be sufficient for a subset of its physiological roles while AKT-S473 phosphorylation is required for other functions [37,38]
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