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Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2016 Jun 01; Vol. 110 (3), pp. 408-18. Date of Electronic Publication: 2016 Mar 21. - Publication Year :
- 2016
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Abstract
- Aims: Reduced homoarginine plasma levels are associated with unfavourable cardiovascular outcome in chronic kidney disease (CKD). Cardiovascular events in CKD are fostered by vascular calcification, an active process promoted by hyperphosphatemia and involving osteo-/chondrogenic transformation of vascular smooth muscle cells (VSMCs). The present study explored the effect of homoarginine on phosphate-induced osteo-/chondrogenic signalling and vascular calcification.<br />Methods and Results: Experiments were performed in hyperphosphatemic klotho-hypomorphic mice (kl/kl), in subtotal nephrectomy and vitamin D3-overload mouse calcification models and in primary human aortic smooth muscle cells (HAoSMCs). As a result, plasma homoarginine levels were lower in kl/kl mice than in wild-type mice and in both genotypes significantly increased by lifelong treatment with homoarginine. Surprisingly, homoarginine treatment of kl/kl mice and of mice with renal failure after subtotal nephrectomy augmented vascular calcification and enhanced the transcript levels of plasminogen activator inhibitor 1 (Pai1) and of osteogenic markers Msx2, Cbfa1, and Alpl. Similarly, homoarginine treatment of HAoSMCs increased phosphate-induced calcium deposition, ALP activity, as well as PAI1, MSX2, CBFA1, and ALPL mRNA levels. Homoarginine alone up-regulated osteo-/chondrogenic signalling and indicators of oxidative stress in HAoSMCs. Furthermore, homoarginine reduced citrulline formation from arginine by nitric oxide (NO) synthase (NOS) isoforms. NO formation by NOS was reduced when using homoarginine as a substrate instead of arginine. The osteoinductive effects of homoarginine were mimicked by NOS inhibitor L-NAME and abolished by additional treatment with the NO donors DETA-NONOate and PAPA-NONOate or the antioxidants TEMPOL and TIRON. Furthermore, homoarginine augmented vascular calcification and aortic osteo-/chondrogenic signalling in mice after vitamin D3-overload, effects reversed by the NO donor molsidomine.<br />Conclusion: Homoarginine augments osteo-/chondrogenic transformation of VSMCs and vascular calcification, effects involving impaired NO formation from homoarginine.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Biomarkers blood
Calcium metabolism
Cells, Cultured
Cholecalciferol
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Expression Regulation drug effects
Genetic Predisposition to Disease
Glucuronidase genetics
Glucuronidase metabolism
Homoarginine blood
Humans
Hyperphosphatemia genetics
Hyperphosphatemia pathology
Klotho Proteins
Mice, Knockout
Muscle, Smooth, Vascular metabolism
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle metabolism
Myocytes, Smooth Muscle pathology
Nephrectomy
Nitric Oxide metabolism
Nitric Oxide Donors pharmacology
Nitric Oxide Synthase antagonists & inhibitors
Nitric Oxide Synthase metabolism
Phenotype
Renal Insufficiency genetics
Renal Insufficiency metabolism
Renal Insufficiency pathology
Time Factors
Vascular Calcification blood
Vascular Calcification genetics
Vascular Calcification pathology
Cell Transdifferentiation drug effects
Chondrogenesis drug effects
Homoarginine toxicity
Hyperphosphatemia metabolism
Muscle, Smooth, Vascular drug effects
Myocytes, Smooth Muscle drug effects
Osteogenesis drug effects
Vascular Calcification chemically induced
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 110
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 27001421
- Full Text :
- https://doi.org/10.1093/cvr/cvw062