| First Author | Elbaz M | Year | 2015 |
| Journal | Cell Death Dis | Volume | 6 |
| Pages | e1690 | PubMed ID | 25766329 |
| Mgi Jnum | J:319105 | Mgi Id | MGI:6862729 |
| Doi | 10.1038/cddis.2015.60 | Citation | Elbaz M, et al. (2015) Life or death by NFkappaB, Losartan promotes survival in dy2J/dy2J mouse of MDC1A. Cell Death Dis 6:e1690 |
| abstractText | 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. |
