Sirtuin 6 Regulates the Activation of the ATP/Purinergic Axis in Endothelial Cells

Author:

Astigiano Cecilia1,Piacente Francesco1ORCID,Laugieri Maria Elena1,Benzi Andrea1,Di Buduo Christian A.2ORCID,Miguel Carolina P.2ORCID,Soncini Debora3ORCID,Cea Michele34ORCID,Antonelli Antonella5ORCID,Magnani Mauro5ORCID,Balduini Alessandra26,De Flora Antonio1,Bruzzone Santina14ORCID

Affiliation:

1. Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy

2. Department of Molecular Medicine, University of Pavia, Via C. Forlanini 6, 27100 Pavia, Italy

3. Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy

4. IRCCS Ospedale Policlinico San Martino, Largo R. Benzi, 16132 Genova, Italy

5. Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi 2, 61029 Urbino, Italy

6. Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA 02155, USA

Abstract

Sirtuin 6 (SIRT6) is a member of the mammalian NAD+-dependent deac(et)ylase sirtuin family. SIRT6’s anti-inflammatory roles are emerging increasingly often in different diseases and cell types, including endothelial cells. In this study, the role of SIRT6 in pro-inflammatory conditions was investigated by engineering human umbilical vein endothelial cells to overexpress SIRT6 (SIRT6+ HUVECs). Our results showed that SIRT6 overexpression affected the levels of adhesion molecules and sustained megakaryocyte proliferation and proplatelet formation. Interestingly, the pro-inflammatory activation of the ATP/purinergic axis was reduced in SIRT6+ HUVECs. Specifically, the TNFα-induced release of ATP in the extracellular space and the increase in pannexin-1 hemichannel expression, which mediates ATP efflux, were hampered in SIRT6+ cells. Instead, NAD+ release and Connexin43 expression were not modified by SIRT6 levels. Moreover, the Ca2+ influx in response to ATP and the expression of the purinergic receptor P2X7 were decreased in SIRT6+ HUVECs. Contrary to extracellular ATP, extracellular NAD+ did not evoke pro-inflammatory responses in HUVECs. Instead, NAD+ administration reduced endothelial cell proliferation and motility and counteracted the TNFα-induced angiogenesis. Altogether, our data reinforce the view of SIRT6 activation as an anti-inflammatory approach in vascular endothelium.

Funder

Italian Ministry of Education, University and Research

Compagnia di San Paolo

University of Genoa

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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