Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine

Ioana Alesutan, Martina Feger, Rashad Tuffaha, Tatsiana Castor, Katharina Musculus, Salvatore S. Buehling, Christian L. Heine, Makoto Kuro-O, Burkert Pieske, Kurt Schmidt, Andreas Tomaschitz, Winfried Maerz, Stefan Pilz, Andreas Meinitzer, Jakob Voelkl, Florian Lang

Research output: Contribution to journalArticle

49 Citations (Scopus)

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. 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. Conclusion Homoarginine augments osteo-/chondrogenic transformation of VSMCs and vascular calcification, effects involving impaired NO formation from homoarginine.

Original languageEnglish (US)
Pages (from-to)408-418
Number of pages11
JournalCardiovascular Research
Volume110
Issue number3
DOIs
StatePublished - Jun 1 2016

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Homoarginine
Vascular Smooth Muscle
Smooth Muscle Myocytes
Phosphates
Vascular Calcification
Nitric Oxide Synthase
Nitric Oxide Donors
Cholecalciferol
Nephrectomy
Chronic Renal Insufficiency
Arginine
Nitric Oxide
Molsidomine
Hyperphosphatemia
Citrulline
Plasminogen Activator Inhibitor 1
NG-Nitroarginine Methyl Ester

Keywords

  • Homoarginine
  • Nitric oxide
  • Osteo-/chondrogenic signalling
  • Vascular calcification
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Alesutan, I., Feger, M., Tuffaha, R., Castor, T., Musculus, K., Buehling, S. S., ... Lang, F. (2016). Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine. Cardiovascular Research, 110(3), 408-418. https://doi.org/10.1093/cvr/cvw062

Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine. / Alesutan, Ioana; Feger, Martina; Tuffaha, Rashad; Castor, Tatsiana; Musculus, Katharina; Buehling, Salvatore S.; Heine, Christian L.; Kuro-O, Makoto; Pieske, Burkert; Schmidt, Kurt; Tomaschitz, Andreas; Maerz, Winfried; Pilz, Stefan; Meinitzer, Andreas; Voelkl, Jakob; Lang, Florian.

In: Cardiovascular Research, Vol. 110, No. 3, 01.06.2016, p. 408-418.

Research output: Contribution to journalArticle

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 2016, 'Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine', Cardiovascular Research, vol. 110, no. 3, pp. 408-418. https://doi.org/10.1093/cvr/cvw062
Alesutan, Ioana ; Feger, Martina ; Tuffaha, Rashad ; Castor, Tatsiana ; Musculus, Katharina ; Buehling, Salvatore S. ; Heine, Christian L. ; Kuro-O, Makoto ; Pieske, Burkert ; Schmidt, Kurt ; Tomaschitz, Andreas ; Maerz, Winfried ; Pilz, Stefan ; Meinitzer, Andreas ; Voelkl, Jakob ; Lang, Florian. / Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine. In: Cardiovascular Research. 2016 ; Vol. 110, No. 3. pp. 408-418.
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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. 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. Conclusion Homoarginine augments osteo-/chondrogenic transformation of VSMCs and vascular calcification, effects involving impaired NO formation from homoarginine.",
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T1 - Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine

AU - Alesutan, Ioana

AU - Feger, Martina

AU - Tuffaha, Rashad

AU - Castor, Tatsiana

AU - Musculus, Katharina

AU - Buehling, Salvatore S.

AU - Heine, Christian L.

AU - Kuro-O, Makoto

AU - Pieske, Burkert

AU - Schmidt, Kurt

AU - Tomaschitz, Andreas

AU - Maerz, Winfried

AU - Pilz, Stefan

AU - Meinitzer, Andreas

AU - Voelkl, Jakob

AU - Lang, Florian

PY - 2016/6/1

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N2 - 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. 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. Conclusion Homoarginine augments osteo-/chondrogenic transformation of VSMCs and vascular calcification, effects involving impaired NO formation from homoarginine.

AB - 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. 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. Conclusion Homoarginine augments osteo-/chondrogenic transformation of VSMCs and vascular calcification, effects involving impaired NO formation from homoarginine.

KW - Homoarginine

KW - Nitric oxide

KW - Osteo-/chondrogenic signalling

KW - Vascular calcification

KW - Vascular smooth muscle cells

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