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Life or death by NFκB, Losartan promotes survival in dy2J/dy2J mouse of MDC1A.

Elbaz M, Yanay N, Laban S, Rabie M, Mitrani-Rosenbaum S, Nevo Y - Cell Death Dis (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.

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.

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Related in: MedlinePlus

Proposed model for NFkB as a key regulator in the survival path of muscle following Losartan treatment. Losartan treatment increases TNF-α, which in turn activates NFκB through IκB-α and IκB-β degradation, p65 nuclear accumulation and upregulation of the pro-survival genes: TRAF1, TRAF2, CIAP2, and FTH1 in addition to anti-apoptotic BCL-2 protein, to mediate the anti-apoptotic effect of NFκB in skeletal muscle of the dy2J/dy2J mouse model of MDC1A. In addition, Losartan treatment results in decreased expression of the pro-apoptotic protein Caspase-3
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fig6: Proposed model for NFkB as a key regulator in the survival path of muscle following Losartan treatment. Losartan treatment increases TNF-α, which in turn activates NFκB through IκB-α and IκB-β degradation, p65 nuclear accumulation and upregulation of the pro-survival genes: TRAF1, TRAF2, CIAP2, and FTH1 in addition to anti-apoptotic BCL-2 protein, to mediate the anti-apoptotic effect of NFκB in skeletal muscle of the dy2J/dy2J mouse model of MDC1A. In addition, Losartan treatment results in decreased expression of the pro-apoptotic protein Caspase-3

Mentions: We therefore suggest a model regarding NFκB signaling activity following Losartan treatment. Losartan treatment results in increasing TNF-α, which in turn activates NFκB through IκB-α and IκB-β degradation, p65 nuclear accumulation and upregulation of pro-survival genes and proteins to mediate the anti-apoptotic effect of NFκB in the dy2J/dy2J mouse model of MDC1A (Figure 6).


Life or death by NFκB, Losartan promotes survival in dy2J/dy2J mouse of MDC1A.

Elbaz M, Yanay N, Laban S, Rabie M, Mitrani-Rosenbaum S, Nevo Y - Cell Death Dis (2015)

Proposed model for NFkB as a key regulator in the survival path of muscle following Losartan treatment. Losartan treatment increases TNF-α, which in turn activates NFκB through IκB-α and IκB-β degradation, p65 nuclear accumulation and upregulation of the pro-survival genes: TRAF1, TRAF2, CIAP2, and FTH1 in addition to anti-apoptotic BCL-2 protein, to mediate the anti-apoptotic effect of NFκB in skeletal muscle of the dy2J/dy2J mouse model of MDC1A. In addition, Losartan treatment results in decreased expression of the pro-apoptotic protein Caspase-3
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385938&req=5

fig6: Proposed model for NFkB as a key regulator in the survival path of muscle following Losartan treatment. Losartan treatment increases TNF-α, which in turn activates NFκB through IκB-α and IκB-β degradation, p65 nuclear accumulation and upregulation of the pro-survival genes: TRAF1, TRAF2, CIAP2, and FTH1 in addition to anti-apoptotic BCL-2 protein, to mediate the anti-apoptotic effect of NFκB in skeletal muscle of the dy2J/dy2J mouse model of MDC1A. In addition, Losartan treatment results in decreased expression of the pro-apoptotic protein Caspase-3
Mentions: We therefore suggest a model regarding NFκB signaling activity following Losartan treatment. Losartan treatment results in increasing TNF-α, which in turn activates NFκB through IκB-α and IκB-β degradation, p65 nuclear accumulation and upregulation of pro-survival genes and proteins to mediate the anti-apoptotic effect of NFκB in the dy2J/dy2J mouse model of MDC1A (Figure 6).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Neuromuscular Laboratory and Neuropediatric Unit, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.

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.

Show MeSH
Related in: MedlinePlus