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Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease
Elena Aikawa1, Masanori Aikawa, Peter Libby
1Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, 149 13th St, Room 5420, Charlestown, MA 02129, USA. eaikawa@mgh.harvard.edu
Insights
Cathepsin S (catS) drives arterial and aortic valve calcification in chronic renal disease (CRD). Inhibiting catS may prevent cardiovascular disease progression in CRD patients.
Area of Science:
- Cardiovascular Biology
- Nephrology
- Molecular Imaging
Background:
- 50% of chronic renal disease (CRD) patients die from cardiovascular causes, often due to calcific arterial and valvular disease.
- Mechanisms of accelerated calcification in CRD are unclear; current therapies cannot prevent progression.
- Inflammation and elastin degradation products are implicated in cardiovascular calcification.
Purpose of the Study:
- To test the in vivo hypothesis that cathepsin S (catS) accelerates calcification in atherosclerotic mice with CRD.
- To investigate the role of catS-induced elastolysis in cardiovascular calcification.
Main Methods:
- Used genetically modified mice (apoE(-/-)/catS(+/+) and apoE(-/-)/catS(-/-)) with surgically induced CRD (5/6 nephrectomy).
- Employed molecular imaging agents to visualize catS activity and osteogenesis in vivo.
- Performed quantitative histology to assess elastin fragmentation and calcification in aortas and aortic valves.
Main Results:
- CRD mice exhibited elevated serum phosphate, creatinine, and cystatin C.
- In vivo imaging revealed increased catS and osteogenic activity in CRD mice lacking catS deletion.
- CRD mice with catS deletion showed significantly less aortic and valvular calcification and elastin fragmentation.
- In vitro studies confirmed that catS and elastin peptides promote smooth muscle cell calcification.
Conclusions:
- Cathepsin S (catS)-induced elastolysis directly accelerates arterial and aortic valve calcification in chronic renal disease (CRD).
- This study provides novel insights into the pathophysiology of cardiovascular calcification in CRD.
- Targeting catS may offer a therapeutic strategy to prevent cardiovascular complications in CRD patients.
Background:
Clinical studies have demonstrated that 50% of individuals with chronic renal disease (CRD) die of cardiovascular causes, including advanced calcific arterial and valvular disease; however, the mechanisms of accelerated calcification in CRD remain obscure, and no therapies can prevent disease progression. We recently demonstrated in vivo that inflammation triggers cardiovascular calcification. In vitro evidence also indicates that elastin degradation products may promote osteogenesis. Here, we used genetically modified mice and molecular imaging to test the hypothesis in vivo that cathepsin S (catS), a potent elastolytic proteinase, accelerates calcification in atherosclerotic mice with CRD induced by 5/6 nephrectomy.
Methods And Results:
Apolipoprotein-deficient (apoE(-/-))/catS(+/+) (n=24) and apoE(-/-)/catS(-/-) (n=24) mice were assigned to CRD and control groups. CRD mice had significantly higher serum phosphate, creatinine, and cystatin C levels than those without CRD. To visualize catS activity and osteogenesis in vivo, we coadministered catS-activatable and calcification-targeted molecular imaging agents 10 weeks after nephrectomy. Imaging coregistered increased catS and osteogenic activities in the CRD apoE(-/-)/catS(+/+) cohort, whereas CRD apoE(-/-)/catS(-/-) mice exhibited less calcification. Quantitative histology demonstrated greater catS-associated elastin fragmentation and calcification in CRD apoE(-/-)/catS(+/+) than CRD apoE(-/-)/catS(-/-) aortas and aortic valves. Notably, catS deletion did not cause compensatory increases in RNA levels of other elastolytic cathepsins or matrix metalloproteinases. Elastin peptide and recombinant catS significantly increased calcification in smooth muscle cells in vitro, a process further amplified in phosphate-enriched culture medium.
Conclusions:
The present study provides direct in vivo evidence that catS-induced elastolysis accelerates arterial and aortic valve calcification in CRD, providing new insight into the pathophysiology of cardiovascular calcification.
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