Sarogni, Patrizia
(2017)
EGFR activation promotes a hypertrophic phenotype in NAGLU depleted cardiomyoblasts, depicting features of mucopolysaccharidosis IIIB.
[Tesi di dottorato]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
EGFR activation promotes a hypertrophic phenotype in NAGLU depleted cardiomyoblasts, depicting features of mucopolysaccharidosis IIIB |
| Autori: |
| Autore | Email |
|---|
| Sarogni, Patrizia | patrizia.sarogni@unina.it |
|
| Data: |
11 Dicembre 2017 |
| Numero di pagine: |
59 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
dep14 |
| Dottorato: |
phd054 |
| Ciclo di dottorato: |
30 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| Avvedimento, Vittorio Enrico | avvedim@unina.it |
|
| Tutor: |
| nome | email |
|---|
| Pavone, Luigi Michele | [non definito] |
|
| Data: |
11 Dicembre 2017 |
| Numero di pagine: |
59 |
| Parole chiave: |
Mucopolysaccharidosis IIIB; NAGLU; Hypertrophy; Lysosomes |
| Settori scientifico-disciplinari del MIUR: |
Area 05 - Scienze biologiche > BIO/10 - Biochimica |
[error in script]
[error in script]
| Depositato il: |
27 Dic 2017 23:37 |
| Ultima modifica: |
20 Mar 2019 09:51 |
| URI: |
http://www.fedoa.unina.it/id/eprint/12189 |
Abstract
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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