Sarogni, Patrizia (2017) EGFR activation promotes a hypertrophic phenotype in NAGLU depleted cardiomyoblasts, depicting features of mucopolysaccharidosis IIIB. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: EGFR activation promotes a hypertrophic phenotype in NAGLU depleted cardiomyoblasts, depicting features of mucopolysaccharidosis IIIB
Date: 11 December 2017
Number of Pages: 59
Institution: Università degli Studi di Napoli Federico II
Department: dep14
Dottorato: phd054
Ciclo di dottorato: 30
Coordinatore del Corso di dottorato:
Avvedimento, Vittorio
Pavone, Luigi MicheleUNSPECIFIED
Date: 11 December 2017
Number of Pages: 59
Keywords: Mucopolysaccharidosis IIIB; NAGLU; Hypertrophy; Lysosomes
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/10 - Biochimica
Date Deposited: 27 Dec 2017 23:37
Last Modified: 20 Mar 2019 09:51

Collection description

Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease due to the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate degradation. Since perturbation of lysosomal homeostasis represents an important cause of cardiomyocyte dysfunction in cardiovascular diseases, we generated a model of the MPS IIIB by silencing NAGLU gene expression in H9C2 rat cardiomyoblasts. NAGLU-depleted H9C2 exhibited accumulation of abnormal lysosomes and a hypertrophic phenotype. Through a phospho-receptor tyrosine kinase array, we found the specific activation of the epidermal growth factor receptor (EGFR) in NAGLU-depleted H9C2 compared to control cells. The pretreatment of NAGLU-depleted H9C2 with the specific EGFR inhibitor AG1478 caused the reduction of both lysosomal aberration and cellular hypertrophy. Similar results were obtained when NAGLU-depleted H9C2 were treated with PD98059, a selective inhibitor of MEK/ERK downstream targets of EGFR. Furthermore, we found increased phosphorylation levels of c-Src in NAGLU-depleted H9C2 where c-Src perturbation affected the hypertrophic response. However, c-Src phosphorylation remained unaffected after treatment of NAGLU-depleted H9C2 clones with AG1478, posing c-Src phosphorylation upstream EGFR activation. Finally, the heparin-binding EGF-like growth factor (HB-EGF) protein resulted to be up-regulated in NAGLU-depleted H9C2, and its silencing caused a reduction of the hypertrophic response. These results demonstrate that both c-Src and HB-EGF may contribute to the hypertrophic phenotype of NAGLU-depleted cardiomyoblasts by activating EGFR signaling, and suggest that the inhibition of EGFR pathway might represent an effective therapeutic strategy for the cure of MPS IIIB cardiac disease.


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