Life or Death by NFκB, Losartan Promotes Survival in Dy2J/dy2J Mouse of MDC1A

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2015 Mar 14

PMID 25766329

Citations 11

Authors

M Elbaz

N Yanay

S Laban

M Rabie

S Mitrani-Rosenbaum

Y Nevo

Affiliations

Soon will be listed here.

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.

Citing Articles

Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins.

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Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy.

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Impaired Regeneration in Dystrophic Muscle-New Target for Therapy.

Yanay N, Rabie M, Nevo Y Front Mol Neurosci. 2020; 13:69.

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A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD.

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Antioxidants Reduce Muscular Dystrophy in the Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy.

Harandi V, Oliveira B, Allamand V, Friberg A, Fontes-Oliveira C, Durbeej M Antioxidants (Basel). 2020; 9(3).

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