Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I.

Abstract

BACKGROUND:

Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease.

METHODS:

Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry.

RESULTS:

Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice.

CONCLUSIONS:

Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker.

• Authors: Omar Khalid, Moin U Vera, Philip L Gordts, N Matthew Ellinwood, Philip H Schwartz, Patricia I Dickson, Jeffrey D Esko, Raymond Y Wang
• Journal: PloS one (PLoS One) Vol. 11 Issue 3 Pg. e0150850 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 26986213 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Clusterin

Topics

• Animals
• Aorta (metabolism, pathology)
• Cardiovascular Diseases (etiology, genetics, pathology)
• Carotid Arteries (immunology, pathology)
• Clusterin (analysis)
• Dogs
• Female
• Gene Expression Regulation
• Gene Regulatory Networks
• Inflammation (complications, genetics)
• Mice, Inbred C57BL
• Mucopolysaccharidosis I (complications, genetics)