PMID- 28340591
OWN - NLM
STAT- MEDLINE
DCOM- 20171130
LR  - 20211204
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 18
IP  - 1
DP  - 2017 Mar 24
TI  - Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular 
      remodeling in monocrotaline-induced pulmonary hypertension.
PG  - 53
LID - 10.1186/s12931-017-0536-7 [doi]
LID - 53
AB  - BACKGROUND: Right ventricular structure and function is a major predictor of 
      outcomes in pulmonary hypertension (PH), yet the underlying mechanisms remain 
      poorly understood. Growing evidence suggests the importance of autophagy in 
      cardiac remodeling; however, its dynamics in the process of right ventricle(RV) 
      remodeling in PH has not been fully explored. We sought to study the time course 
      of cardiomyocyte autophagy in the RV in PH and determine whether mammalian target 
      of rapamycin (mTOR) and Beclin-1 hypoxia-related pro-autophagic pathways are 
      underlying mechanisms. METHODS: Rats were studied at 2, 4, and 6 weeks after 
      subcutaneous injection of 60 mg/kg monocrotaline (MCT) (MCT-2 W, 4 W, 6 W) or 
      vehicle (CON-2 W, 4 W, 6 W). Cardiac hemodynamics and RV function were assessed 
      in rats. Autophagy structures and markers were assessed using transmission 
      electron microscope, RT-qPCR, immunohistochemistry staining, and western blot 
      analyses. Western blot was also used to quantify the expression of mTOR and 
      Beclin-1 mediated pro-autophagy signalings in the RV. RESULTS: Two weeks after 
      MCT injection, pulmonary artery systolic pressure increased and mild RV 
      hypertrophy without RV dilation was observed. RV enlargement presented at 4 weeks 
      with moderately decreased function, whereas typical characteristics of RV 
      decompensation and failure occurred at 6 weeks thus demonstrating the progression 
      of RV remodeling in the MCT model. A higher LC3 (microtubule- associated protein 
      light chain 3) II/I ratio, upregulated LC3 mRNA and protein levels, as well as 
      accumulation of autophagosomes in RV of MCT rats indicated autophagy induction. 
      Autophagy activation was coincident with increased pulmonary artery systolic 
      pressure. Pro-autophagy signaling pathways were activated in a RV remodeling 
      stage-dependent manner since phospho-AMPK (adenosine monophosphate-activated 
      protein kinase)-alpha were primarily upregulated and phospho-mTOR suppressed in the 
      RV at 2 and 4 weeks post-MCT injection, whearas, BNIP3 (Bcl2-interacting protein 
      3) and beclin-1 expression were relatively low during these stages, they were 
      significantly upregulated after 6 weeks in this model. CONCLUSIONS: Our findings 
      provide evidence of sustained activation of autophagy in RV remodeling of MCT 
      induced PH model, while pro-autophagic signaling pathways varied depending on the 
      phase.
FAU - Deng, Yan
AU  - Deng Y
AD  - Department of Ultrasound, First Affiliated Hospital of Guangxi Medical 
      University, Nanning, People's Republic of China.
FAU - Wu, Weifeng
AU  - Wu W
AD  - Department of Cardiology, First Affiliated Hospital of Guangxi Medical 
      University, 6 Shuangyong Road, Nanning, 530021, People's Republic of China. 
      wucna65@163.com.
FAU - Guo, Shenglan
AU  - Guo S
AD  - Department of Ultrasound, First Affiliated Hospital of Guangxi Medical 
      University, Nanning, People's Republic of China.
FAU - Chen, Yuming
AU  - Chen Y
AD  - Department of Cardiology, First Affiliated Hospital of Guangxi Medical 
      University, 6 Shuangyong Road, Nanning, 530021, People's Republic of China.
FAU - Liu, Chang
AU  - Liu C
AD  - Department of Cardiology, First Affiliated Hospital of Guangxi Medical 
      University, 6 Shuangyong Road, Nanning, 530021, People's Republic of China.
FAU - Gao, Xingcui
AU  - Gao X
AD  - Department of Cardiology, First Affiliated Hospital of Guangxi Medical 
      University, 6 Shuangyong Road, Nanning, 530021, People's Republic of China.
FAU - Wei, Bin
AU  - Wei B
AD  - Department of Cardiology, First Affiliated Hospital of Guangxi Medical 
      University, 6 Shuangyong Road, Nanning, 530021, People's Republic of China.
LA  - eng
PT  - Journal Article
DEP - 20170324
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (Beclin-1)
RN  - 0 (Becn1 protein, rat)
RN  - 73077K8HYV (Monocrotaline)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - *Autophagy
MH  - Beclin-1/*metabolism
MH  - Hypertension, Pulmonary/chemically induced/pathology/*physiopathology
MH  - Male
MH  - Monocrotaline
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Ventricular Dysfunction, Right/chemically induced/pathology/*physiopathology
MH  - *Ventricular Remodeling
PMC - PMC5366117
OTO - NOTNLM
OT  - Autophagy
OT  - Cardiac remodeling
OT  - Monocrotaline
OT  - Pulmonary hypertension
OT  - Right ventricular
EDAT- 2017/03/28 06:00
MHDA- 2017/12/01 06:00
PMCR- 2017/03/24
CRDT- 2017/03/26 06:00
PHST- 2016/09/13 00:00 [received]
PHST- 2017/03/12 00:00 [accepted]
PHST- 2017/03/26 06:00 [entrez]
PHST- 2017/03/28 06:00 [pubmed]
PHST- 2017/12/01 06:00 [medline]
PHST- 2017/03/24 00:00 [pmc-release]
AID - 10.1186/s12931-017-0536-7 [pii]
AID - 536 [pii]
AID - 10.1186/s12931-017-0536-7 [doi]
PST - epublish
SO  - Respir Res. 2017 Mar 24;18(1):53. doi: 10.1186/s12931-017-0536-7.