title: Life or death by NFκB, Losartan promotes survival in dy2J/dy2J mouse of MDC1A.
abstract: Inflammation and fibrosis are well-defined mechanisms involved in the pathogenesis of the incurable Laminin α2-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-β) 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 (NFκB) 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-α) level, p65 nuclei accumulation, and decreased muscle IκB-β protein level, indicating NFκB activation. Moreover, NFκB 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-β and MAPK signaling, NFκB serves as an important regulatory pathway which following Losartan treatment promotes survival in the dy(2J)/dy(2J) mouse model of MDC1A.
authors.affiliation: Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Elbaz
authors.affiliation: Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Yanay
authors.affiliation: Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Laban
authors.affiliation: Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Rabie
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Mitrani-Rosenbaum
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Nevo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005293:Ferritins / Q000096:biosynthesis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D019808:Losartan / Q000008:administration & dosage; D051379:Mice; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics*; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000096:biosynthesis* / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C498144:Rela protein, mouse; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D051996:Transcription Factor RelA; D005293:Ferritins; D053148:Caspase 3; D019808:Losartan