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SHR Neuro Krebs Kardio Lipid Stoffw 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]
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Co-Autor*innen der Med Uni Graz

März Winfried

Meinitzer Andreas

Pieske Burkert Mathias

Pilz Stefan

Tomaschitz Andreas

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Abstract:

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: journals.permissions@oup.com.

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)

Homoarginine

Nitric oxide

Vascular calcification

Osteo-

chondrogenic signalling

Vascular smooth muscle cells

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