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Elastolytic activity of cysteine cathepsins K, S, and V promotes vascular calcification.

ABSTRACT: Elastin plays an important role in maintaining blood vessel integrity. Proteolytic degradation of elastin in the vascular system promotes the development of atherosclerosis, including blood vessel calcification. Cysteine cathepsins have been implicated in this process, however, their role in disease progression and associated complications remains unclear. Here, we showed that the degradation of vascular elastin by cathepsins (Cat) K, S, and V directly stimulates the mineralization of elastin and that mineralized insoluble elastin fibers were ~25-30% more resistant to CatK, S, and V degradation when compared to native elastin. Energy dispersive X-ray spectroscopy investigations showed that insoluble elastin predigested by CatK, S, or V displayed an elemental percentage in calcium and phosphate up to 8-fold higher when compared to non-digested elastin. Cathepsin-generated elastin peptides increased the calcification of MOVAS-1 cells acting through the ERK1/2 pathway by 34-36%. We made similar observations when cathepsin-generated elastin peptides were added to ex vivo mouse aorta rings. Altogether, our data suggest that CatK-, S-, and V-mediated elastolysis directly accelerates the mineralization of the vascular matrix by the generation of nucleation points in the elastin matrix and indirectly by elastin-derived peptides stimulating the calcification by vascular smooth muscle cells. Both processes inversely protect against further extracellular matrix degradation.

SUBMITTER: Andrault PM

PROVIDER: S-EPMC6609650 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Elastolytic activity of cysteine cathepsins K, S, and V promotes vascular calcification.

Andrault Pierre-Marie PM Panwar Preety P Mackenzie Neil C W NCW Brömme Dieter D

Scientific reports 20190704 1

Elastin plays an important role in maintaining blood vessel integrity. Proteolytic degradation of elastin in the vascular system promotes the development of atherosclerosis, including blood vessel calcification. Cysteine cathepsins have been implicated in this process, however, their role in disease progression and associated complications remains unclear. Here, we showed that the degradation of vascular elastin by cathepsins (Cat) K, S, and V directly stimulates the mineralization of elastin an ...[more]

PMID: 31273243

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Project description:ObjectiveVascular calcification is a characteristic feature of atherosclerosis, diabetes mellitus, and end-stage renal disease. We have demonstrated that activation of protein kinase B (AKT) upregulates runt-related transcription factor 2 (Runx2), a key osteogenic transcription factor that is crucial for calcification of vascular smooth muscle cells (VSMC). Using mice with SMC-specific deletion of phosphatase and tensin homolog (PTEN), a major negative regulator of AKT, the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO (forkhead box O)-mediated Runx2 upregulation and VSMC calcification.Approach and resultsSMC-specific PTEN deletion mice were generated by crossing PTEN floxed mice with SM22α-Cre transgenic mice. The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo. Runx2 knockdown did not affect proliferation but blocked calcification of the PTEN-deficient VSMC, suggesting that PTEN deletion promotes Runx2-depedent VSMC calcification that is independent of proliferation. At the molecular level, PTEN deficiency increased the amount of Runx2 post-transcriptionally by inhibiting Runx2 ubiquitination. AKT activation increased phosphorylation of FOXO1/3 that led to nuclear exclusion of FOXO1/3. FOXO1/3 knockdown in VSMC phenocopied the PTEN deficiency, demonstrating a novel function of FOXO1/3, as a downstream signaling of PTEN/AKT, in regulating Runx2 ubiquitination and VSMC calcification. Using heterozygous SMC-specific PTEN-deficient mice and atherogenic ApoE(-/-) mice, we further demonstrated AKT activation, FOXO phosphorylation, and Runx2 ubiquitination in vascular calcification in vivo.ConclusionsOur studies have determined a new causative effect of SMC-specific PTEN deficiency on vascular calcification and demonstrated that FOXO1/3 plays a crucial role in PTEN/AKT-modulated Runx2 ubiquitination and VSMC calcification.

Project description: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.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.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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Elastolytic activity of cysteine cathepsins K, S, and V promotes vascular calcification.

Publications

Elastolytic activity of cysteine cathepsins K, S, and V promotes vascular calcification.

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