PMID- 24825564
OWN - NLM
STAT- MEDLINE
DCOM- 20141020
LR  - 20211203
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Linking)
VI  - 229
IP  - 12
DP  - 2014 Dec
TI  - mTORC1 is involved in hypoxia-induced pulmonary hypertension through the 
      activation of Notch3.
PG  - 2117-25
LID - 10.1002/jcp.24670 [doi]
AB  - Hypoxia-induced pulmonary hypertension (HPH) is a clinical syndrome associated 
      with high morbidity and mortality. However, the underlying mechanisms remain 
      unclear. Both the mammalian target of rapamycin (mTOR) and the Notch3 signaling 
      pathways have been reported to be involved in HPH; however, it is unknown whether 
      there is a connection between these two signaling pathways in HPH. This study was 
      designed to investigate the relationship between mTOR and Notch3 in HPH. After 
      treatment with 10% O2 for 4 weeks, male C57BL/6 mice developed HPH with gradually 
      increased right ventricular systolic pressure (RVSP), right ventricular 
      hypertrophy index (RVHI), and pulmonary arteriolar remodeling accompanied by the 
      activation of mTOR complex 1 (mTORC1) and Notch3 in the lung tissue and pulmonary 
      arterioles. Pretreatment with the mTORC1 inhibitor rapamycin not only alleviated 
      pulmonary arterial pressure and pulmonary arteriolar remodeling but also 
      suppressed hypoxia-induced mTORC1 and Notch3 activation. Prophylactic 
      N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) 
      administration, a Notch signaling inhibitor, protected against the effects of 
      hypoxia. These in vivo data were confirmed by in vitro experiments on human 
      pulmonary arterial smooth muscle cell (PASMC) exposed to 3% O2 . Furthermore, 
      overexpression of Notch3 intracellular domain partially abrogated the inhibitory 
      effects of rapamycin on human PASMC proliferation. These data indicate that both 
      mTORC1 and Notch3 signaling are involved in HPH and the downstream effects of 
      mTORC1 activation in HPH are partially dependent on the activation of Notch3 
      signaling.
CI  - (c) 2014 Wiley Periodicals, Inc.
FAU - Wang, Wang
AU  - Wang W
AD  - Department of Physiology, Capital Medical University, Beijing, P.R. China.
FAU - Liu, Jie
AU  - Liu J
FAU - Ma, Aiping
AU  - Ma A
FAU - Miao, Ran
AU  - Miao R
FAU - Jin, Yuling
AU  - Jin Y
FAU - Zhang, Hongbing
AU  - Zhang H
FAU - Xu, Kaifeng
AU  - Xu K
FAU - Wang, Chen
AU  - Wang C
FAU - Wang, Jun
AU  - Wang J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Dipeptides)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester)
RN  - 0 (Notch3 protein, mouse)
RN  - 0 (Receptor, Notch3)
RN  - 0 (Receptors, Notch)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Cell Proliferation/drug effects
MH  - Dipeptides/administration & dosage
MH  - Humans
MH  - Hypertension, Pulmonary/*genetics/pathology
MH  - Hypertrophy, Right Ventricular/metabolism/pathology
MH  - Hypoxia/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes/genetics/*metabolism
MH  - Myocytes, Smooth Muscle/metabolism/pathology
MH  - Oxygen/*administration & dosage
MH  - Receptor, Notch3
MH  - Receptors, Notch/genetics/*metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
EDAT- 2014/05/16 06:00
MHDA- 2014/10/21 06:00
CRDT- 2014/05/15 06:00
PHST- 2013/12/19 00:00 [received]
PHST- 2014/05/09 00:00 [accepted]
PHST- 2014/05/15 06:00 [entrez]
PHST- 2014/05/16 06:00 [pubmed]
PHST- 2014/10/21 06:00 [medline]
AID - 10.1002/jcp.24670 [doi]
PST - ppublish
SO  - J Cell Physiol. 2014 Dec;229(12):2117-25. doi: 10.1002/jcp.24670.