Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension
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 and Ayako Makino
Raptor (mTORC1) in Smooth Muscle Cells and Pulmonary Hypertension
SM-specific conditional and inducible KO of Raptor attenuates hypoxia-induced pulmonary hypertension in RaptorSM−/− mice. (A) Schematic strategy for the generation of RaptorSM–/– mice (a); Western blot analysis of Raptor (regulatory associated protein of mammalian target of rapamycin) in isolated PA from WT and RaptorSM−/− mice (b); and the timeline indicating the time for Tam injection (to induce Raptor KO), hypoxic exposure (to induce PH), and experimental measurements (c). (B) Representative immunofluorescence images showing cell nuclei (DAPI; blue), smooth muscle cells (SMA; red), and Raptor (dark green) in the cross-section of small PA in lung tissues from WT (Raptor-Oil) and RaptorSM−/− (Raptor-Tam) mice (a). Summarized data (mean ± SE; n = 3 in each group) for DAPI, SMA, and Raptor fluorescence intensity are shown in b. Student’s t-test, ***p < 0.001 versus Raptor-Oil. (C) Representative record of RVP (a) as well as summarized data (mean ± SE) showing the peak value of RVSP (b) (Kruskal-Wallis test, p < 0.001) and the Fulton index (RV/[LV + S]) ratio (c) (Kruskal-Wallis test, p < 0.001) in WT (Oil-Cre+/RaptorF/F) and RaptorSM−/− (Tam-Cre+/RaptorF/F) mice exposed to normoxia (room air, 21% oxygen) and hypoxia (10% oxygen for 3 weeks). Dunn test, ***p < 0.001, **p < 0.01 versus Normoxia-WT; #p < 0.05 versus Hypoxia WT. The numbers of experiments (n) for each group are indicated in each bar. Abbreviations as in Figure 1.