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Integrin Dysregulation as a Driver of Matrix Remodeling in a Model of Congenital Muscular Dystrophy
Author(s) -
Accorsi Anthony,
Mehuron Thomas,
Kumar Ajay,
Rhee Younghwa,
Girgenrath Mahasweta
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.719.18
Subject(s) - congenital muscular dystrophy , laminin , integrin , muscular dystrophy , extracellular matrix , biology , transforming growth factor beta , fibrosis , signal transduction , microbiology and biotechnology , cancer research , transforming growth factor , immunology , medicine , pathology , receptor , biochemistry , genetics
Laminin‐deficient congenital muscular dystrophy (MDC1A) is the second most prevalent form of muscular dystrophy and is caused by a defect in the alpha chain of the muscle specific extracellular matrix protein Laminin‐211. Loss of this protein leads to vast signaling defects leading to failed regeneration, inflammation, fibrosis, and apoptosis. While the genetic cause is known, distinct pathomechanisms have yet to be elucidated. Integrins are heterodimeric membrane proteins that play key roles in many critical cell processes including cell adhesion and signal transduction. However, when dysregulated, they have been shown to be key pathological drivers in many disease scenarios. Using the DyW mouse model of MDC1A, qRT‐PCR, ELISA, and immunohistochemistry, we show for the first time that integrins, and most importantly Integrin‐αV, which is known to activate Transforming Growth Factor‐beta (TGF‐β) in fibrotic scenarios, are dysregulated in dystrophic muscle. Further, we found that protein levels of both latent and active TGF‐β are upregulated in the serum of DyW mice but only active TGF‐β is attenuated in response to treatment with Losartan (Angiotensin II type 1 receptor blocker known to be a potent antifibrotic agent). Interestingly, along with reduced levels of active TGF‐β, we also see a rescue of Integrin‐αV overexpression. Therefore, it is possible that the attenuation of TGF‐β signaling by Losartan could be mediated by downregulation of Integrin‐αV. These results suggest Integrin‐αV could be an important player in the induction and mediation of fibrotic pathology in MDC1A and could serve as a novel therapeutic target in this and other fibrotic, degenerative diseases.