PMID- 25766329
OWN - NLM
STAT- MEDLINE
DCOM- 20151130
LR  - 20211110
IS  - 2041-4889 (Electronic)
VI  - 6
IP  - 3
DP  - 2015 Mar 12
TI  - Life or death by NFkappaB, Losartan promotes survival in dy2J/dy2J mouse of MDC1A.
PG  - e1690
LID - 10.1038/cddis.2015.60 [doi]
AB  - Inflammation and fibrosis are well-defined mechanisms involved in the 
      pathogenesis of the incurable Laminin alpha2-deficient congenital muscular dystrophy 
      (MDC1A), while apoptosis mechanism is barely discussed. Our previous study showed 
      treatment with Losartan, an angiotensin II type I receptor antagonist, improved 
      muscle strength and reduced fibrosis through transforming growth factor beta 
      (TGF-beta) and mitogen-activated protein kinases (MAPK) signaling inhibition in the 
      dy(2J)/dy(2J) mouse model of MDC1A. Here we show for the first time that Losartan 
      treatment up-regulates and shifts the nuclear factor kappa B (NFkappaB) signaling 
      pathway to favor survival versus apoptosis/damage in this animal model. Losartan 
      treatment was associated with significantly increased serum tumor necrosis factor 
      alpha (TNF-alpha) level, p65 nuclei accumulation, and decreased muscle IkappaB-beta protein 
      level, indicating NFkappaB activation. Moreover, NFkappaB anti-apoptotic target genes TNF 
      receptor-associated factor 1 (TRAF1), TNF receptor-associated factor 2 (TRAF2), 
      cellular inhibitor of apoptosis (cIAP2), and Ferritin heavy chain (FTH1) were 
      increased following Losartan treatment. Losartan induced protein expression 
      toward a pro-survival profile as BCL-2 expression levels were increased and 
      Caspase-3 expression levels were decreased. Muscle apoptosis reduction was 
      further confirmed using terminal deoxynucleotidyltransferase-mediated dUTP nick 
      end labeling (TUNEL) assay. Thus, along with TGF-beta and MAPK signaling, NFkappaB 
      serves as an important regulatory pathway which following Losartan treatment 
      promotes survival in the dy(2J)/dy(2J) mouse model of MDC1A.
FAU - Elbaz, M
AU  - Elbaz M
AD  - Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Yanay, N
AU  - Yanay N
AD  - Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Laban, S
AU  - Laban S
AD  - Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Rabie, M
AU  - Rabie M
AD  - Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Mitrani-Rosenbaum, S
AU  - Mitrani-Rosenbaum S
AD  - Goldyne Savad Institute of Gene Therapy, Hadassah - Hebrew University Medical 
      Center, Jerusalem, Israel.
FAU - Nevo, Y
AU  - Nevo Y
AD  - 1] Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew 
      University Medical Center, Jerusalem, Israel [2] Institute of Neurology, 
      Schneider Children's Medical Center of Israel, 14 Kaplan St., Petach Tikva, 
      Israel.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150312
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Rela protein, mouse)
RN  - 0 (TNF Receptor-Associated Factor 1)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Transcription Factor RelA)
RN  - 9007-73-2 (Ferritins)
RN  - EC 3.4.22.- (Caspase 3)
RN  - JMS50MPO89 (Losartan)
RN  - Muscular dystrophy congenital, merosin negative
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspase 3/metabolism
MH  - Disease Models, Animal
MH  - Ferritins/biosynthesis
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins/biosynthesis
MH  - Losartan/administration & dosage
MH  - Mice
MH  - Muscle Strength/drug effects
MH  - Muscle, Skeletal/drug effects/metabolism/pathology
MH  - Muscular Dystrophies/drug therapy/*genetics/pathology
MH  - NF-kappa B/*genetics
MH  - Signal Transduction
MH  - TNF Receptor-Associated Factor 1/*biosynthesis/genetics
MH  - TNF Receptor-Associated Factor 2/*biosynthesis/genetics
MH  - Transcription Factor RelA/metabolism
PMC - PMC4385938
EDAT- 2015/03/15 06:00
MHDA- 2015/12/15 06:00
PMCR- 2015/03/01
CRDT- 2015/03/14 06:00
PHST- 2014/11/24 00:00 [received]
PHST- 2015/01/26 00:00 [revised]
PHST- 2015/01/27 00:00 [accepted]
PHST- 2015/03/14 06:00 [entrez]
PHST- 2015/03/15 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2015/03/01 00:00 [pmc-release]
AID - cddis201560 [pii]
AID - 10.1038/cddis.2015.60 [doi]
PST - epublish
SO  - Cell Death Dis. 2015 Mar 12;6(3):e1690. doi: 10.1038/cddis.2015.60.