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SHR Neuro Cancer Cardio Lipid Metab Microb

Alesutan, I; Feger, M; Tuffaha, R; Castor, T; Musculus, K; Buehling, SS; Heine, CL; Kuro-O, M; Pieske, B; Schmidt, K; Tomaschitz, A; Maerz, W; Pilz, S; Meinitzer, A; Voelkl, J; Lang, F.
Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine.
Cardiovasc Res. 2016; 110(3):408-418 Doi: 10.1093/cvr/cvw062 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG


Co-authors Med Uni Graz
März Winfried
Meinitzer Andreas
Pieske Burkert Mathias
Pilz Stefan
Tomaschitz Andreas

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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. 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. Homoarginine augments osteo-/chondrogenic transformation of VSMCs and vascular calcification, effects involving impaired NO formation from homoarginine. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email:
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Biomarkers - blood
Calcium - metabolism
Cell Transdifferentiation - drug effects
Cells, Cultured -
Cholecalciferol -
Chondrogenesis - drug effects
Disease Models, Animal -
Dose-Response Relationship, Drug -
Gene Expression Regulation - drug effects
Genetic Predisposition to Disease -
Glucuronidase - genetics
Glucuronidase - metabolism
Homoarginine - blood
Homoarginine - toxicity
Humans -
Hyperphosphatemia - genetics
Hyperphosphatemia - metabolism
Hyperphosphatemia - pathology
Mice, Knockout -
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Myocytes, Smooth Muscle - drug effects
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
Osteogenesis - drug effects
Phenotype -
Renal Insufficiency - genetics
Renal Insufficiency - metabolism
Renal Insufficiency - pathology
Time Factors -
Vascular Calcification - blood
Vascular Calcification - chemically induced
Vascular Calcification - genetics
Vascular Calcification - pathology

Find related publications in this database (Keywords)
Nitric oxide
Vascular calcification
chondrogenic signalling
Vascular smooth muscle cells
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