TY - JOUR
T1 - Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction
T2 - Insights in patients with diabetes
AU - Paneni, Francesco
AU - Costantino, Sarah
AU - Castello, Lorenzo
AU - Battista, Rodolfo
AU - Capretti, Giuliana
AU - Chiandotto, Sergio
AU - D'Amario, Domenico
AU - Scavone, Giuseppe
AU - Villano, Angelo
AU - Rustighi, Alessandra
AU - Crea, Filippo
AU - Pitocco, Dario
AU - Lanza, Gaetano
AU - Volpe, Massimo
AU - Del Sal, Giannino
AU - Lüscher, Thomas F.
AU - Cosentino, Francesco
N1 - Funding Information:
This study was supported by grants from the Swiss Heart Foundation, Italian Ministry of Education, University and Research, PRIN 2010-2011 (to F.C.), and the Swiss National Research Foundation to T.F.L (3100-06811802/1). AIRC Special Program Molecular Clinical Oncology ‘5 per mille’ and Italian Ministry of University and Research (RBAP10XKNC_003 and PRIN 2009-2009YP9AE5) to G.D.S. F.P was the recipient of a PhD programme in Experimental Medicine at the University of Rome ‘Sapienza’.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Aim: Diabetes is a major driver of cardiovascular disease, but the underlying mechanisms remain elusive. Prolyl-isomerase Pin1 recognizes specific peptide bonds and modulates function of proteins altering cellular homoeostasis. The present study investigates Pin1 role in diabetes-induced vascular disease. Methods and results: In human aortic endothelial cells (HAECs) exposed to high glucose, up-regulation of Pin1-inducedmitochondrial translocation of pro-oxidant adaptor p66Shc and subsequent organelle disruption. In this setting, Pin1 recognizes Ser-116 inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) leading to eNOS-caveolin-1 interaction and reducedNOavailability. Pin1 also mediates hyperglycaemia-induced nuclear translocation of NF-kB p65, triggering VCAM-1, ICAM-1, and MCP-1 expression. Indeed, gene silencing of Pin1 in HAECs suppressed p66Shcdependent ROS production, restored NO release and blunted NF-kB p65 nuclear translocation. Consistently, diabetic Pin1-/- micewere protected againstmitochondrial oxidative stress, endothelial dysfunction, and vascular inflammation. Increased expression and activity of Pin1 were also found in peripheral blood monocytes isolated from diabetic patients when compared with age-matched healthy controls. Interestingly, enough, Pin1 up-regulation was associated with impaired flow-mediated dilation, increased urinary 8-iso-prostaglandin F2α and plasma levels of adhesion molecules. Conclusions: Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kBinduced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes. Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2014.
AB - Aim: Diabetes is a major driver of cardiovascular disease, but the underlying mechanisms remain elusive. Prolyl-isomerase Pin1 recognizes specific peptide bonds and modulates function of proteins altering cellular homoeostasis. The present study investigates Pin1 role in diabetes-induced vascular disease. Methods and results: In human aortic endothelial cells (HAECs) exposed to high glucose, up-regulation of Pin1-inducedmitochondrial translocation of pro-oxidant adaptor p66Shc and subsequent organelle disruption. In this setting, Pin1 recognizes Ser-116 inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) leading to eNOS-caveolin-1 interaction and reducedNOavailability. Pin1 also mediates hyperglycaemia-induced nuclear translocation of NF-kB p65, triggering VCAM-1, ICAM-1, and MCP-1 expression. Indeed, gene silencing of Pin1 in HAECs suppressed p66Shcdependent ROS production, restored NO release and blunted NF-kB p65 nuclear translocation. Consistently, diabetic Pin1-/- micewere protected againstmitochondrial oxidative stress, endothelial dysfunction, and vascular inflammation. Increased expression and activity of Pin1 were also found in peripheral blood monocytes isolated from diabetic patients when compared with age-matched healthy controls. Interestingly, enough, Pin1 up-regulation was associated with impaired flow-mediated dilation, increased urinary 8-iso-prostaglandin F2α and plasma levels of adhesion molecules. Conclusions: Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kBinduced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes. Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2014.
KW - Diabetes mellitus
KW - Endothelial function
KW - Inflammation
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=84926674364&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehu179
DO - 10.1093/eurheartj/ehu179
M3 - Article
SN - 0195-668X
VL - 36
SP - 817
EP - 828
JO - European Heart Journal
JF - European Heart Journal
IS - 13
ER -