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mTOR‐Notch3 signaling mediates pulmonary hypertension in hypoxia‐exposed neonatal rats independent of changes in autophagy
Author(s) -
Ivanovska Julijana,
Shah Sparsh,
Wong Mathew J.,
Kantores Crystal,
Jain Amish,
Post Martin,
Yeganeh Behzad,
Jankov Robert P.
Publication year - 2017
Publication title -
pediatric pulmonology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.866
H-Index - 106
eISSN - 1099-0496
pISSN - 8755-6863
DOI - 10.1002/ppul.23777
Subject(s) - autophagy , pi3k/akt/mtor pathway , notch signaling pathway , medicine , hypoxia (environmental) , sirolimus , pulmonary hypertension , signal transduction , cancer research , pharmacology , microbiology and biotechnology , biology , receptor , chemistry , apoptosis , biochemistry , organic chemistry , oxygen
Background/Aim Mammalian target of rapamycin (mTOR) is a pivotal regulator of cell proliferation, survival, and autophagy. Autophagy is increased in adult experimental chronic pulmonary hypertension (PHT), but its contributory role to pulmonary vascular disease remains uncertain and has yet to be explored in the neonatal animal. Notch is a major pro‐proliferative pathway activated by mTOR. A direct relationship between autophagy and Notch signaling has not been previously explored. Our aim was to examine changes in mTOR‐, Notch‐, and autophagy‐related pathways and the therapeutic effects of autophagy modulators in experimental chronic neonatal PHT secondary to chronic hypoxia. Methods Rat pups were exposed to normoxia or hypoxia (13% O 2 ) from postnatal days 1‐21, while receiving treatment with temsirolimus (mTOR inhibitor), DAPT (Notch inhibitor), or chloroquine (inhibitor of autophagic flux). Results Exposure to hypoxia up‐regulated autophagy and Notch3 signaling markers in lung, pulmonary artery (PA), and PA‐derived smooth muscle cells (SMCs). Temsirolimus prevented chronic PHT and attenuated PA and SMC signaling secondary to hypoxia. These effects were replicated by DAPT. mTOR or Notch inhibition also down‐regulated smooth muscle content of platelet‐derived growth factor β‐receptor, a known contributor to vascular remodeling. In contrast, chloroquine had no modifying effects on markers of chronic PHT. Knockdown of Beclin‐1 in SMCs had no effect on hypoxia‐stimulated Notch3 signaling. Conclusions mTOR‐Notch3 signaling plays a critical role in experimental chronic neonatal PHT. Inhibition of autophagy did not suppress Notch signaling and had no effect on markers of chronic PHT.