PMID- 28679058
OWN - NLM
STAT- MEDLINE
DCOM- 20171207
LR  - 20220318
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 57
IP  - 5
DP  - 2017 Nov
TI  - Pharmacological Inhibition of mTOR Kinase Reverses Right Ventricle Remodeling and 
      Improves Right Ventricle Structure and Function in Rats.
PG  - 615-625
LID - 10.1165/rcmb.2016-0364OC [doi]
AB  - Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular 
      remodeling, increased pulmonary artery (PA) pressure, right-heart afterload and 
      death. Mechanistic target of rapamycin (mTOR) promotes smooth muscle cell 
      proliferation, survival, and pulmonary vascular remodeling via two functionally 
      distinct mTOR complexes (mTORCs)-1 (supports cell growth) and -2 (promotes cell 
      survival), and dual mTORC1/mTORC2 inhibition selectively induces pulmonary 
      arterial hypertension PA vascular smooth muscle cell apoptosis and reverses 
      pulmonary vascular remodeling. The consequences of mTOR inhibition on right 
      ventricle (RV) morphology and function are not known. Using SU5416/hypoxia rat 
      model of pulmonary hypertension (PH), we report that, in contrast to activation 
      of both mTORC1 and mTORC2 pathways in small remodeled PAs, RV tissues had 
      predominant up-regulation of mTORC1 signaling accompanied by cardiomyocyte and RV 
      hypertrophy, increased RV wall thickness, RV/left ventricle end-diastolic area 
      ratio, RV contractility and afterload (arterial elastance), and shorter RV 
      acceleration time compared with controls. Treatment with mTOR kinase inhibitor, 
      PP242, at Weeks 6-8 after PH induction suppressed both mTORC1 and mTORC2 in small 
      PAs, but only mTORC1 signaling in RV, preserving basal mTORC2-Akt levels. 
      Vehicle-treated rats showed further PH and RV worsening and profound RV fibrosis. 
      PP242 reversed pulmonary vascular remodeling and prevented neointimal occlusion 
      of small PAs, significantly reduced PA pressure and pulmonary vascular 
      resistance, reversed cardiomyocyte hypertrophy and RV remodeling, improved max RV 
      contractility, arterial elastance, and RV acceleration time, and prevented 
      development of RV fibrosis. Collectively, these data show a predominant role of 
      mTORC1 versus mTORC2 in RV pathology, and suggest potential attractiveness of 
      mTOR inhibition to simultaneously target pulmonary vascular remodeling and RV 
      dysfunction in established PH.
FAU - Pena, Andressa
AU  - Pena A
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
FAU - Kobir, Ahasanul
AU  - Kobir A
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
FAU - Goncharov, Dmitry
AU  - Goncharov D
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
FAU - Goda, Akiko
AU  - Goda A
AD  - 2 Division of Cardiology.
FAU - Kudryashova, Tatiana V
AU  - Kudryashova TV
AUID- ORCID: 0000-0002-2843-5554
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
FAU - Ray, Arnab
AU  - Ray A
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
FAU - Vanderpool, Rebecca
AU  - Vanderpool R
AD  - 3 Department of Medicine, University of Arizona, Tuscon, Arizona.
FAU - Baust, Jeffrey
AU  - Baust J
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
FAU - Chang, Baojun
AU  - Chang B
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
FAU - Mora, Ana L
AU  - Mora AL
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
AD  - 4 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of 
      Medicine, and.
FAU - Gorcsan, John 3rd
AU  - Gorcsan J 3rd
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
AD  - 2 Division of Cardiology.
FAU - Goncharova, Elena A
AU  - Goncharova EA
AUID- ORCID: 0000-0001-7118-6752
AD  - 1 Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute.
AD  - 4 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of 
      Medicine, and.
AD  - 5 Department of Bioengineering, University of Pittsburgh, Pittsburgh, 
      Pennsylvania; and.
LA  - eng
GR  - P01 HL103455/HL/NHLBI NIH HHS/United States
GR  - R01 HL113178/HL/NHLBI NIH HHS/United States
GR  - R24 HL123767/HL/NHLBI NIH HHS/United States
GR  - T32 HL110849/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Indoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrroles)
RN  - 71IA9S35AJ (Semaxinib)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - doi: 10.1165/rcmb.2017-0245ED
MH  - Animals
MH  - Cell Proliferation/drug effects/physiology
MH  - Cell Survival/drug effects/physiology
MH  - Hypertension, Pulmonary/drug therapy
MH  - Hypertrophy, Right Ventricular/metabolism/*physiopathology
MH  - Indoles/pharmacology
MH  - Male
MH  - Myocytes, Cardiac/metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Pulmonary Artery/drug effects/metabolism/physiopathology
MH  - Pyrroles/pharmacology
MH  - Rats, Sprague-Dawley
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Ventricular Remodeling/*drug effects
PMC - PMC5705904
OTO - NOTNLM
OT  - mechanistic target of rapamycin complex 1
OT  - mechanistic target of rapamycin complex 2
OT  - mechanistic target of rapamycin kinase inhibitor
OT  - pulmonary hypertension
OT  - right ventricle
EDAT- 2017/07/06 06:00
MHDA- 2017/12/08 06:00
PMCR- 2018/11/01
CRDT- 2017/07/06 06:00
PHST- 2017/07/06 06:00 [pubmed]
PHST- 2017/12/08 06:00 [medline]
PHST- 2017/07/06 06:00 [entrez]
PHST- 2018/11/01 00:00 [pmc-release]
AID - 10.1165/rcmb.2016-0364OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2017 Nov;57(5):615-625. doi: 10.1165/rcmb.2016-0364OC.