Cathepsin B inhibition attenuates cardiovascular pathology in mucopolysaccharidosis I mice

Life Sci. 2018 Mar 1;196:102-109. doi: 10.1016/j.lfs.2018.01.020. Epub 2018 Jan 31.


Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder with multisystemic features, including heart enlargement, heart valve dysfunction, and aortic stiffness and dilatation. Previous studies have shown that MPS I mice overexpress cathepsin B (CtsB) in multiple tissues, including those from the cardiovascular system. Here, we hypothesized that inhibition of CtsB could ameliorate cardiac function parameters, as well as aorta and valve abnormalities found in MPS I. First, we found that total elastase activity in an MPS I aorta is elevated. Following that, we demonstrated that CtsB leaks from the lysosome in MPS I human fibroblasts, possibly acting as a degradative agent of extracellular matrix components from the aorta, cardiac muscle, and heart valves. We then used a CtsB inhibitor in vivo in the MPS I mouse model. After 4 months of treatment, partial inhibition of CtsB activity in treated mice reduced aortic dilatation, as well as heart valve thickening, and led to improvements in cardiac function parameters, although none of these were completely normalized. Based on these results, we conclude that lysosomal alterations in this disease promote leakage of CtsB to outside the organelle, where this protein can have multiple pathological roles. CtsB inhibition improved cardiovascular parameters in MPS I mice and can have a potential benefit in this disease.

Keywords: Ca-074 Me; Cardiovascular disease; Cathepsin B; Mucopolysaccharidosis type I.

MeSH terms

  • Animals
  • Aorta / pathology
  • Aorta / physiopathology
  • Cardiovascular System / diagnostic imaging
  • Cardiovascular System / pathology*
  • Cathepsin B / antagonists & inhibitors*
  • Cathepsin B / metabolism
  • Collagenases / metabolism
  • Cysteine Proteinase Inhibitors / therapeutic use*
  • Dipeptides / therapeutic use*
  • Female
  • Fibroblasts / metabolism
  • Heart Function Tests
  • Heart Valve Diseases / diagnostic imaging
  • Heart Valve Diseases / drug therapy
  • Heart Valve Diseases / pathology
  • Humans
  • Lysosomes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mucopolysaccharidosis I / diagnostic imaging*
  • Mucopolysaccharidosis I / drug therapy*
  • Mucopolysaccharidosis I / pathology
  • Pancreatic Elastase / metabolism


  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline
  • Pancreatic Elastase
  • Cathepsin B
  • Collagenases