Title |
Sirtuin 1 regulates pulmonary artery smooth muscle cell proliferation
|
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Published in |
Journal of Hypertension, May 2018
|
DOI | 10.1097/hjh.0000000000001676 |
Pubmed ID | |
Authors |
Giada Zurlo, Jérôme Piquereau, Maryline Moulin, Julie Pires Da Silva, Mélanie Gressette, Benoît Ranchoux, Anne Garnier, Renée Ventura-Clapier, Elie Fadel, Marc Humbert, Christophe Lemaire, Frédéric Perros, Vladimir Veksler |
Abstract |
Energy metabolism shift from oxidative phosphorylation toward glycolysis in pulmonary artery smooth muscle cells (PASMCs) is suggested to be involved in their hyperproliferation in pulmonary arterial hypertension (PAH). Here, we studied the role of the deacetylase sirtuin1 (SIRT1) in energy metabolism regulation in PASMCs via various pathways including activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), master regulator of mitochondrial biogenesis. Contents of PGC-1α and its downstream targets as well as markers of mitochondrial mass (voltage-dependent anion channel and citrate synthase) were diminished in human PAH PASMCs. These cells and platelet-derived growth factor-stimulated rat PASMCs demonstrated a shift in cellular acetylated/deacetylated state, as evidenced by the increase of the acetylated forms of SIRT1 targets: histone H1 and Forkhead box protein O1. Rat and human PASMC proliferation was potentiated by SIRT1 pharmacological inhibition or specific downregulation via short-interfering RNA. Moreover, after chronic hypoxia exposure, SIRT1 inducible knock out mice displayed a more intense vascular remodeling compared with their control littermates, which was associated with an increase in right ventricle pressure and hypertrophy. SIRT1 activator Stac-3 decreased the acetylation of histone H1 and Forkhead box protein O1 and strongly inhibited rat and human PASMC proliferation without affecting cell mortality. This effect was associated with the activation of mitochondrial biogenesis evidenced by higher expression of mitochondrial markers and downstream targets of PGC-1α. Altered acetylation/deacetylation balance as the result of SIRT1 inactivation is involved in the pathogenesis of PAH, and this enzyme could be a promising therapeutic target for PAH treatment. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 4 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 50% |
Science communicators (journalists, bloggers, editors) | 2 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 35 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 7 | 20% |
Student > Bachelor | 4 | 11% |
Student > Master | 4 | 11% |
Researcher | 3 | 9% |
Professor > Associate Professor | 3 | 9% |
Other | 6 | 17% |
Unknown | 8 | 23% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 12 | 34% |
Agricultural and Biological Sciences | 6 | 17% |
Medicine and Dentistry | 4 | 11% |
Immunology and Microbiology | 1 | 3% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 3% |
Other | 0 | 0% |
Unknown | 11 | 31% |