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Eur Heart J. 2015 Apr 1;36(13):817-28. doi: 10.1093/eurheartj/ehu179. Epub 2014 May 5.

Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes.

Author information

  • 1Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden IRCCS Neuromed, Pozzilli, Italy.
  • 2Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden.
  • 3Cardiology, Department of Clinical and Molecular Medicine, University of Rome 'Sapienza', Rome, Italy.
  • 4Internal Medicine Unit, Civil Hospital, Sora, Italy.
  • 5Department of Cardiovascular Medicine, Catholic University, Rome, Italy.
  • 6Diabetes Care Unit, Internal Medicine, Catholic University, Rome, Italy.
  • 7Laboratorio Nazionale CIB, AREA Science Park and Department of Life Sciences, University of Trieste, Trieste, Italy.
  • 8IRCCS Neuromed, Pozzilli, Italy Cardiology, Department of Clinical and Molecular Medicine, University of Rome 'Sapienza', Rome, Italy.
  • 9Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland.
  • 10Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden francesco.cosentino@ki.se.

Abstract

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-induced mitochondrial translocation of pro-oxidant adaptor p66(Shc) 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 reduced NO availability. Pin1 also mediates hyperglycaemia-induced nuclear translocation of NF-κB p65, triggering VCAM-1, ICAM-1, and MCP-1 expression. Indeed, gene silencing of Pin1 in HAECs suppressed p66(Shc)-dependent ROS production, restored NO release and blunted NF-kB p65 nuclear translocation. Consistently, diabetic Pin1(-/-) mice were protected against mitochondrial 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-kB-induced 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. For permissions please email: journals.permissions@oup.com.

KEYWORDS:

Diabetes mellitus; Endothelial function; Inflammation; Oxidative stress

[PubMed - indexed for MEDLINE]
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