1. Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension
- Author
-
Ayako Makino, Ankit A. Desai, Ramon J. Ayon, Yali Gu, Ziyi Wang, Qian Zhang, Guofei Zhou, Shanshan Song, Franz Rischard, Jiwang Chen, Jason X.-J. Yuan, Kang Wu, Sujana Vinjamuri, Angela Balistrieri, Haiyang Tang, Rebecca Vanderpool, Joe G.N. Garcia, Jian Wang, and Stephen M. Black more...
- Subjects
phosphatase and tensin homolog ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Raptor, regulatory associated protein of mammalian target of rapamycin ,PH ,Rictor, rapamycin insensitive companion of mammalian target of rapamycin ,mTORC1 ,right ventricle ,Pharmacology ,Cardiovascular ,PI3K ,mTORC2 ,platelet-derived growth factor ,smooth muscle ,PRECLINICAL RESEARCH ,GPCR ,0302 clinical medicine ,pulmonary arterial hypertension ,PASMC ,Lung ,PDGFR, platelet-derived growth factor receptor ,WT ,mTORC1, mammalian target of rapamycin complex 1 ,rapamycin insensitive companion of mammalian target of rapamycin ,HPH, hypoxia-induced pulmonary hypertension ,PAEC ,3. Good health ,pulmonary arterial endothelial cell ,TKR ,endothelial cell ,Cardiology and Cardiovascular Medicine ,PA ,Clinical Sciences ,phosphorylated AKT ,03 medical and health sciences ,Right ventricular hypertrophy ,pulmonary artery ,G protein-coupled receptor ,GPCR, G protein-coupled receptor ,pulmonary arterial smooth muscle cell ,EC, endothelial cell ,mammalian target of rapamycin complex 2 ,mammalian target of rapamycin complex 1 ,medicine.disease ,pAKT, phosphorylated AKT ,WT, wild-type ,030104 developmental biology ,lcsh:RC666-701 ,0301 basic medicine ,PTEN ,PVR ,Cardiorespiratory Medicine and Haematology ,030204 cardiovascular system & hematology ,PDGF, platelet-derived growth factor ,SM, smooth muscle ,RVSP ,hypoxia-induced pulmonary hypertension ,RVSP, right ventricular systolic pressure ,pulmonary hypertension ,right ventricular hypertrophy ,regulatory associated protein of mammalian target of rapamycin ,SM ,phosphoinositide 3-kinase ,PDGF ,PAEC, pulmonary arterial endothelial cell ,Raptor ,PA, pulmonary artery ,Heart Disease ,medicine.anatomical_structure ,HPH ,pulmonary vascular resistance ,mTORC2, mammalian target of rapamycin complex 2 ,mTOR ,PAH, pulmonary arterial hypertension ,PI3K, phosphoinositide 3-kinase ,PASMC, pulmonary arterial smooth muscle cell ,PDGFR ,Forkhead box O3a ,pAKT ,PH, pulmonary hypertension ,PVR, pulmonary vascular resistance ,Rictor ,FOXO3a, Forkhead box O3a ,Rare Diseases ,Growth factor receptor ,TKR, tyrosine kinase receptor ,medicine ,right ventricular systolic pressure ,FOXO3a ,PI3K/AKT/mTOR pathway ,wild-type ,EC ,business.industry ,RVH, right ventricular hypertrophy ,PAH ,platelet-derived growth factor receptor ,Pulmonary hypertension ,PTEN, phosphatase and tensin homolog ,Vascular resistance ,tyrosine kinase receptor ,business ,RVH - Abstract
Visual Abstract, Highlights • G protein-coupled receptors and tyrosine kinase receptors signal through the phosphoinositide 3-kinase/Akt/mTOR pathway to induce cell proliferation, survival, and growth. mTOR is a kinase present in 2 functionally distinct complexes, mTORC1 and mTORC2. • Functional disruption of mTORC1 by knockout of Raptor (regulatory associated protein of mammalian target of rapamycin) in smooth muscle cells ameliorated the development of experimental PH. • Functional disruption of mTORC2 by knockout of Rictor (rapamycin insensitive companion of mammalian target of rapamycin) caused spontaneous PH by up-regulating platelet-derived growth factor receptors. • Use of mTOR inhibitors (e.g., rapamycin) to treat PH should be accompanied by inhibitors of platelet-derived growth factor receptors (e.g., imatinib)., Summary 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. more...
- Published
- 2018
- Full Text
- View/download PDF