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JACC Basic Transl Sci. 2018 Dec 31;3(6):744-762. doi: 10.1016/j.jacbts.2018.08.009. eCollection 2018 Dec.

Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension.

Author information

1
Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
2
State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
3
Department of Physiology, The University of Arizona College of Medicine, Tucson, Arizona.
4
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The University of Arizona College of Medicine, Tucson, Arizona.
5
Department of Pediatrics, University of Illinois College of Medicine, Chicago, Illinois.
6
Division of Cardiology, Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona.

Abstract

Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure.

KEYWORDS:

EC, endothelial cell; FOXO3a, Forkhead box O3a; GPCR, G protein-coupled receptor; HPH, hypoxia-induced pulmonary hypertension; PA, pulmonary artery; PAEC, pulmonary arterial endothelial cell; PAH, pulmonary arterial hypertension; PASMC, pulmonary arterial smooth muscle cell; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PH, pulmonary hypertension; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; PVR, pulmonary vascular resistance; RVH, right ventricular hypertrophy; RVSP, right ventricular systolic pressure; Raptor; Raptor, regulatory associated protein of mammalian target of rapamycin; Rictor; Rictor, rapamycin insensitive companion of mammalian target of rapamycin; SM, smooth muscle; TKR, tyrosine kinase receptor; WT, wild-type; mTOR; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; pAKT, phosphorylated AKT; pulmonary hypertension; right ventricle

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