Author + information
- Received June 11, 2018
- Revision received June 23, 2018
- Accepted August 16, 2018
- Published online December 31, 2018.
- Haiyang Tang, PhDa,b,∗,
- Kang Wu, MD, PhDa,b,∗,
- Jian Wang, MDa,b,∗,
- Sujana Vinjamuri, MD, MSa,
- Yali Gu, MS, RNa,
- Shanshan Song, MD, PhDa,
- Ziyi Wang, MDa,b,
- Qian Zhang, MDa,b,c,
- Angela Balistrieria,
- Ramon J. Ayon, PhDa,
- Franz Rischard, MDa,d,
- Rebecca Vanderpool, PhDa,
- Jiwang Chen, PhDe,
- Guofei Zhou, PhDb,e,
- Ankit A. Desai, MDa,f,
- Stephen M. Black, PhDa,c,
- Joe G.N. Garcia, MDa,c,d,
- Jason X.-J. Yuan, MD, PhDa,b,c and
- Ayako Makino, PhDa,c,∗ ()
- aDivision of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona
- bState Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- cDepartment of Physiology, The University of Arizona College of Medicine, Tucson, Arizona
- dDivision of Pulmonary, Allergy, Critical Care and Sleep Medicine, The University of Arizona College of Medicine, Tucson, Arizona
- eDepartment of Pediatrics, University of Illinois College of Medicine, Chicago, Illinois
- fDivision of Cardiology, Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona
- ↵∗Address for correspondence:
Dr. Ayako Makino, Department of Physiology, The University of Arizona, 1501 North Campbell Avenue, P.O. Box 245051, Tucson, Arizona 85724.
• 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).
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.
↵∗ Drs. Tang, Wu, and Wang contributed equally to this work and are joint first authors.
This work was supported in part by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health (HL135807, HL142214, and HL125208). Dr. Garcia is the founder, CEO, and majority shareholder of Agualung Therapeutics, Corp. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received June 11, 2018.
- Revision received June 23, 2018.
- Accepted August 16, 2018.
- 2018 The Authors