PMID- 27551443
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20160823
LR  - 20200930
IS  - 2058-7716 (Print)
IS  - 2058-7716 (Electronic)
IS  - 2058-7716 (Linking)
VI  - 1
DP  - 2015
TI  - Rap1-mediated nuclear factor-kappaB (NF-kappaB) activity regulates the paracrine 
      capacity of mesenchymal stem cells in heart repair following infarction.
PG  - 15007
LID - 10.1038/cddiscovery.2015.7 [doi]
AB  - Paracrine effect is the major mechanism that underlies mesenchymal stem cells 
      (MSC)-based therapy. This study aimed to examine how Rap1, telomeric 
      repeat-binding factor 2-interacting protein 1 (Terf2IP), which is a novel 
      modulator involved in the nuclear factor-kappaB (NF-kappaB) pathway, regulates the 
      paracrine effects of MSC-mediated heart repair following infarction. NF-kappaB 
      activity of stromal cells was increased by Rap1 as measured by pNF-kappaB-luciferase 
      reporter activity, and this was abolished by IkB-dominant-negative protein. 
      Knockdown of Rap1 with shRap1 resulted in diminished translocation of p65-NF-kappaB 
      from the cytoplasm to nuclei in response to tumor necrosis factor-alpha (TNF-alpha) 
      stimulation. Compared with BM-MSCs, Rap1(-/-)-BM-MSCs displayed a significantly 
      reduced ratio of phosphorylated NF-kappaB to NF-kappaB-p65 and of Bax to Bcl-2, and 
      increased resistance to hypoxia-induced apoptosis by the terminal 
      deoxynucleotidal transferase-mediated dUTP nick end labeling (TUNEL) assay. In 
      contrast, re-expression of Rap1 in Rap1(-/-)-BM-MSCs resulted in loss of 
      resistance to apoptosis in the presence of hypoxia. Moreover, absence of Rap1 in 
      BM-MSCs led to downregulation of NF-kappaB activity accompanied by reduced 
      pro-inflammatory paracrine cytokines TNF-alpha, IL (interleukin)-6 and monocyte 
      chemotactic protein-1 in Rap1(-/-)-BM-MSCs compared with BM-MSCs. The apoptosis 
      of neonatal cardiomyocytes (NCMCs) induced by hypoxia was significantly reduced 
      when cocultured with Rap1(-/-)-BM-MSC hypoxic-conditioned medium (CdM). The 
      increased cardioprotective effects of Rap1(-/-)-BM-MSCs were reduced when 
      Rap1(-/-)-BM-MSCs were reconstituted with Rap1 re-expression. Furthermore, in 
      vivo study showed that transplantation of Rap1(-/-)-BM-MSCs significantly 
      improved heart function, decreased infarct size, prevented cardiomyocyte 
      apoptosis and inhibited inflammation compared with controls and BM-MSCs (P<0.01). 
      This study reveals that Rap1 has a critical role in the regulation of MSC 
      paracrine actions. Compared with BM-MSCs, Rap1(-/-)-BM-MSCs decreased NF-kappaB 
      sensitivity to stress-induced pro-inflammatory cytokine production and reduced 
      apoptosis. Selective inhibition of Rap1 in BM-MSCs may be a novel strategy to 
      enhance MSC-based therapeutic efficacy in myocardial infarction.
FAU - Zhang, Y
AU  - Zhang Y
AD  - Division of Cardiology, Department of Medicine, The University of Hong Kong , 
      Hong Kong SAR, China.
FAU - Chiu, S
AU  - Chiu S
AD  - Division of Cardiology, Department of Medicine, The University of Hong Kong , 
      Hong Kong SAR, China.
FAU - Liang, X
AU  - Liang X
AD  - Division of Cardiology, Department of Medicine, The University of Hong Kong , 
      Hong Kong SAR, China.
FAU - Gao, F
AU  - Gao F
AD  - Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of 
      Hong Kong , Hong Kong SAR, China.
FAU - Zhang, Z
AU  - Zhang Z
AD  - Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of 
      Hong Kong , Hong Kong SAR, China.
FAU - Liao, S
AU  - Liao S
AD  - Division of Cardiology, Department of Medicine, The University of Hong Kong , 
      Hong Kong SAR, China.
FAU - Liang, Y
AU  - Liang Y
AD  - Division of Cardiology, Department of Medicine, The University of Hong Kong , 
      Hong Kong SAR, China.
FAU - Chai, Y-H
AU  - Chai YH
AD  - Division of Cardiology, Department of Medicine, The University of Hong Kong , 
      Hong Kong SAR, China.
FAU - Low, D J H
AU  - Low DJ
AD  - Institute of Molecular and Cellular Biology , Biopolis, Singapore.
FAU - Tse, H-F
AU  - Tse HF
AD  - Division of Cardiology, Department of Medicine, The University of Hong Kong, Hong 
      Kong SAR, China; Research Centre of Heart, Brain, Hormone, and Healthy Aging, Li 
      Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
FAU - Tergaonkar, V
AU  - Tergaonkar V
AD  - Institute of Molecular and Cellular Biology , Biopolis, Singapore.
FAU - Lian, Q
AU  - Lian Q
AD  - Division of Cardiology, Department of Medicine, The University of Hong Kong, Hong 
      Kong SAR, China; Research Centre of Heart, Brain, Hormone, and Healthy Aging, Li 
      Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; 
      Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of 
      Hong Kong, Hong Kong SAR, China; Shenzhen University Health Science Center, 
      Shenzhen, China.
LA  - eng
PT  - Journal Article
DEP - 20150824
PL  - United States
TA  - Cell Death Discov
JT  - Cell death discovery
JID - 101665035
PMC - PMC4981000
EDAT- 2015/01/01 00:00
MHDA- 2015/01/01 00:01
PMCR- 2015/08/24
CRDT- 2016/08/24 06:00
PHST- 2015/06/03 00:00 [received]
PHST- 2015/06/05 00:00 [accepted]
PHST- 2016/08/24 06:00 [entrez]
PHST- 2015/01/01 00:00 [pubmed]
PHST- 2015/01/01 00:01 [medline]
PHST- 2015/08/24 00:00 [pmc-release]
AID - cddiscovery20157 [pii]
AID - 10.1038/cddiscovery.2015.7 [doi]
PST - epublish
SO  - Cell Death Discov. 2015 Aug 24;1:15007. doi: 10.1038/cddiscovery.2015.7. 
      eCollection 2015.