Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension.

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.

• Authors: Haiyang Tang, Kang Wu, Jian Wang, Sujana Vinjamuri, Yali Gu, Shanshan Song, Ziyi Wang, Qian Zhang, Angela Balistrieri, Ramon J Ayon, Franz Rischard, Rebecca Vanderpool, Jiwang Chen, Guofei Zhou, Ankit A Desai, Stephen M Black, Joe G N Garcia, Jason X-J Yuan, Ayako Makino
• Journal: JACC. Basic to translational science (JACC Basic Transl Sci) Vol. 3 Issue 6 Pg. 744-762 (Dec 2018) ISSN: 2452-302X [Electronic] United States
• PMID: 30623134 (Publication Type: Journal Article)