Cargando…
Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling
Vascular calcification is associated with significant morbidity and mortality within diabetes, involving activation of osteogenic regulators and transcription factors. Recent evidence demonstrates the beneficial role of Sirtuin 1 (SIRT1), an NAD(+) dependant deacetylase, in improved insulin sensitiv...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351547/ https://www.ncbi.nlm.nih.gov/pubmed/30696833 http://dx.doi.org/10.1038/s41598-018-37027-2 |
_version_ | 1783390595103850496 |
---|---|
author | Bartoli-Leonard, F. Wilkinson, F. L. Schiro, A. Inglott, F. Serracino Alexander, M. Y. Weston, R. |
author_facet | Bartoli-Leonard, F. Wilkinson, F. L. Schiro, A. Inglott, F. Serracino Alexander, M. Y. Weston, R. |
author_sort | Bartoli-Leonard, F. |
collection | PubMed |
description | Vascular calcification is associated with significant morbidity and mortality within diabetes, involving activation of osteogenic regulators and transcription factors. Recent evidence demonstrates the beneficial role of Sirtuin 1 (SIRT1), an NAD(+) dependant deacetylase, in improved insulin sensitivity and glucose homeostasis, linking hyperglycaemia and SIRT1 downregulation. This study aimed to determine the role of SIRT1 in vascular smooth muscle cell (vSMC) calcification within the diabetic environment. An 80% reduction in SIRT1 levels was observed in patients with diabetes, both in serum and the arterial smooth muscle layer, whilst both RUNX2 and Osteocalcin levels were elevated. Human vSMCs exposed to hyperglycaemic conditions in vitro demonstrated enhanced calcification, which was positively associated with the induction of cellular senescence, verified by senescence-associated β-galactosidase activity and cell cycle markers p16 and p21. Activation of SIRT1 by SRT1720 reduced Alizarin red staining by a third, via inhibition of the RUNX2 pathway and prevention of senescence. Conversely, inhibition of SIRT1 via Sirtinol and siRNA increased RUNX2 by over 50%. These findings demonstrate the key role that SIRT1 plays in preventing calcification in a diabetic environment, through the inhibition of RUNX2 and senescence pathways, suggesting a downregulation of SIRT1 may be responsible for perpetuating vascular calcification in diabetes. |
format | Online Article Text |
id | pubmed-6351547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63515472019-01-30 Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling Bartoli-Leonard, F. Wilkinson, F. L. Schiro, A. Inglott, F. Serracino Alexander, M. Y. Weston, R. Sci Rep Article Vascular calcification is associated with significant morbidity and mortality within diabetes, involving activation of osteogenic regulators and transcription factors. Recent evidence demonstrates the beneficial role of Sirtuin 1 (SIRT1), an NAD(+) dependant deacetylase, in improved insulin sensitivity and glucose homeostasis, linking hyperglycaemia and SIRT1 downregulation. This study aimed to determine the role of SIRT1 in vascular smooth muscle cell (vSMC) calcification within the diabetic environment. An 80% reduction in SIRT1 levels was observed in patients with diabetes, both in serum and the arterial smooth muscle layer, whilst both RUNX2 and Osteocalcin levels were elevated. Human vSMCs exposed to hyperglycaemic conditions in vitro demonstrated enhanced calcification, which was positively associated with the induction of cellular senescence, verified by senescence-associated β-galactosidase activity and cell cycle markers p16 and p21. Activation of SIRT1 by SRT1720 reduced Alizarin red staining by a third, via inhibition of the RUNX2 pathway and prevention of senescence. Conversely, inhibition of SIRT1 via Sirtinol and siRNA increased RUNX2 by over 50%. These findings demonstrate the key role that SIRT1 plays in preventing calcification in a diabetic environment, through the inhibition of RUNX2 and senescence pathways, suggesting a downregulation of SIRT1 may be responsible for perpetuating vascular calcification in diabetes. Nature Publishing Group UK 2019-01-29 /pmc/articles/PMC6351547/ /pubmed/30696833 http://dx.doi.org/10.1038/s41598-018-37027-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Bartoli-Leonard, F. Wilkinson, F. L. Schiro, A. Inglott, F. Serracino Alexander, M. Y. Weston, R. Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling |
title | Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling |
title_full | Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling |
title_fullStr | Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling |
title_full_unstemmed | Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling |
title_short | Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling |
title_sort | suppression of sirt1 in diabetic conditions induces osteogenic differentiation of human vascular smooth muscle cells via runx2 signalling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351547/ https://www.ncbi.nlm.nih.gov/pubmed/30696833 http://dx.doi.org/10.1038/s41598-018-37027-2 |
work_keys_str_mv | AT bartolileonardf suppressionofsirt1indiabeticconditionsinducesosteogenicdifferentiationofhumanvascularsmoothmusclecellsviarunx2signalling AT wilkinsonfl suppressionofsirt1indiabeticconditionsinducesosteogenicdifferentiationofhumanvascularsmoothmusclecellsviarunx2signalling AT schiroa suppressionofsirt1indiabeticconditionsinducesosteogenicdifferentiationofhumanvascularsmoothmusclecellsviarunx2signalling AT inglottfserracino suppressionofsirt1indiabeticconditionsinducesosteogenicdifferentiationofhumanvascularsmoothmusclecellsviarunx2signalling AT alexandermy suppressionofsirt1indiabeticconditionsinducesosteogenicdifferentiationofhumanvascularsmoothmusclecellsviarunx2signalling AT westonr suppressionofsirt1indiabeticconditionsinducesosteogenicdifferentiationofhumanvascularsmoothmusclecellsviarunx2signalling |