Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

Abstract

Mucopolysaccharidosis I (MPS I), known as Hurler syndrome in the severe form, is a lysosomal storage disease due to -L-iduronidase (IDUA) deficiency. It results in fragmentation of elastin fibers in the aorta and heart valves via mechanisms that are unclear, but may result from the accumulation of the glycosaminoglycans heparan and dermatan sulfate. Elastin fragmentation causes aortic dilatation and valvular insufficiency, which can result in cardiovascular disease. The pathophysiology of aortic disease was evaluated in MPS I mice. MPS I mice have normal elastic fiber structure and aortic compliance at early ages, which suggests that elastin assembly is normal. Elastin fragmentation and aortic dilatation are severe at 6 months, which is temporally associated with marked increases in mRNA and enzyme activity for two elastin-degrading proteins, matrix metalloproteinase-12 (MMP-12) and cathepsin S. Upregulation of these genes likely involves activation of STAT proteins, which may be induced by structural stress to smooth muscle cells from accumulation of glycosaminoglycans in lysosomes. Neonatal intravenous injection of a retroviral vector normalized MMP-12 and cathepsin S mRNA levels and prevented aortic disease. We conclude that aortic dilatation in MPS I mice is likely due to degradation of elastin by MMP-12 and/or cathepsin S. This aspect of disease might be ameliorated by inhibition of the signal transduction pathways that upregulate expression of elastase proteins, or by inhibition of elastase activity. This could result in a treatment for patients with MPS I, and might reduce aortic aneurism formation in other disorders.

The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

“…It is also known that accumulated dermatan sulfate can activate STAT proteins which increase productions of elastindegrading proteins, i.e., matrix metalloproteinase-12 (MMP-12) and cathepsin S. (Ma et al 2008). Reduction of elastin in myocardial cells, endocardium, and the coronary artery may lead to proliferation of connective tissues, resulting in fibrosis in the ventricular walls, endocardium, and vascular walls (Hinek and Wilson 2000;Karnik et al 2003).…”

Sub‐pleural bullous changes in two adults with Mucopolysaccharidosis type I (Hurler‐Scheie)

“…Figure 2a and b Patient 2): CT images were of poor quality due to body habitus and breathing artefact; however, subsequent pathology specimens demonstrated bullous macroscopic changes and sub-pleural emphysema microscopically. The sub-pleural distribution of these changes was striking and has not previously been described in patients with MPS type I. Degradation of elastin secondary to increased cathepsin, elastase and matrix metalloproteinase activity has been demonstrated in cell culture and animal models of MPS I, and it seems likely that the same disease process is occurring here (Hinek and Wilson 2000;Ma et al 2008;Metcalf et al 2010). We suggest that screening for subpleural and paraseptal emphysema is warranted in adults with MPS I as there is a risk of lifethreatening spontaneous pneumothorax.…”

Recombinant Encapsulated Cells Overexpressing Alpha-<i>L</i>-Iduronidase Correct Enzyme Deficiency in Human Mucopolysaccharidosis Type I Cells

“…Treatment options currently available for MPS I have been shown to be very ineffective in treating some aspects of the disease, including the aorta, bone, joint and brain [Ma et al, 2008;Wraith, 2009]. Reaching these organs is imperative to improve the quality of life in MPS I patients.…”