Abstract
Mucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disease caused by the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The defective lysosomal clearance of undigested HS results in dysfunction of multiple tissues and organs. We recently demonstrated that the murine model of MPS IIIB develops cardiac disease, valvular abnormalities, and ultimately heart failure. To address the molecular mechanisms governing cardiac dysfunctions in MPS IIIB, we generated a model of the disease by silencing NAGLU gene expression in H9C2 rat cardiomyoblasts. NAGLU-depleted H9C2 exhibited accumulation of abnormal lysosomes and a hypertrophic phenotype. Furthermore, we found the specific activation of the epidermal growth factor receptor (EGFR), and increased phosphorylation levels of extracellular signal-regulated kinases (ERKs) in NAGLU-depleted H9C2. The inhibition of either EGFR or ERKs, using the selective inhibitors AG1478 and PD98059, resulted in the reduction of both lysosomal aberration and hypertrophy in NAGLU-depleted H9C2. We also found increased phosphorylation of c-Src and a reduction of the hypertrophic response in NAGLU-depleted H9C2 transfected with a dominant-negative c-Src. However, c-Src phosphorylation remained unaffected by AG1478 treatment, posing c-Src upstream EGFR activation. Finally, heparin-binding EGF-like growth factor (HB-EGF) protein was found overexpressed in our MPS IIIB cellular model, and its silencing reduced the hypertrophic response. These results indicate that both c-Src and HB-EGF contribute to the hypertrophic phenotype of NAGLU-depleted cardiomyoblasts by synergistically activating EGFR and subsequent signaling, thus suggesting that EGFR pathway inhibition could represent an effective therapeutic approach for MPS IIIB cardiac disease.
Highlights
Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, belonging to the class of lysosomal storage diseases, caused by the deficiency of lysosomal enzymes required to metabolize glycosaminoglycans (GAGs)[1]
Since impaired digestion of heparan sulfate (HS) in MPS IIIB results in the accumulation of the undegraded substrate and consequent lysosomal enlargement, we investigated whether NAGLU depletion is sufficient to induce aberrant lysosomal accumulation in our cellular model
We first established that NAGLU silencing in H9C2 rat cardiomyoblasts fully recapitulates the MPS IIIB lysosomal phenotype and reproduces the hypertrophic phenotype previously detected in the cardiac tissues of NAGLU knockout mice[24]
Summary
Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, belonging to the class of lysosomal storage diseases, caused by the deficiency of lysosomal enzymes required to metabolize glycosaminoglycans (GAGs)[1]. The GAG family includes four main subgroups: hyaluronic acid or hyaluronan (HA), keratan sulfate (KS), Official journal of the Cell Death Differentiation Association. De Pasquale et al Cell Death and Disease (2018)9:40 chondroitin/dermatan sulfate (CS/DS), and heparan sulfate (HS)/heparin. MPSs (MPS I, II, III, IV, VI, VII, and IX), where the accumulation of the undegraded GAG results in multiple organ dysfunctions, with distinct clinical manifestations depending on the type of the lacking enzyme and the accumulated substrate[1]. MPS patients show profound mental retardation, intractable behavior, skeletal abnormalities, cardiovascular dysfunction, and death in the second decade of life[1]. Cardiac disease has been commonly observed in MPS patients and contributes to the early mortality of these patients[3,4,5,6]
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