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

Francesco Paneni, Sarah Costantino, Lorenzo Castello, Rodolfo Battista, Giuliana Capretti, Sergio Chiandotto, Domenico D'Amario, Giuseppe Scavone, Angelo Villano, Alessandra Rustighi, Filippo Crea, Dario Pitocco, Gaetano Lanza, Massimo Volpe, Giannino Del Sal, Thomas F. Lüscher, Francesco Cosentino

Research output: Contribution to journalArticle

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-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 F 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.

Original languageEnglish
Pages (from-to)817-828
Number of pages12
JournalEuropean Heart Journal
Volume36
Issue number13
DOIs
Publication statusPublished - Apr 1 2015

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Peptidylprolyl Isomerase
Nitric Oxide Synthase Type III
Blood Vessels
Oxidative Stress
NF-kappa B
Up-Regulation
Endothelial Cells
Inflammation
Caveolin 1
Diabetic Angiopathies
Dinoprost
Vascular Cell Adhesion Molecule-1
Gene Silencing
Intercellular Adhesion Molecule-1
Vascular Diseases
Hyperglycemia
Organelles
Dilatation
Monocytes
Reactive Oxygen Species

Keywords

  • Diabetes mellitus
  • Endothelial function
  • Inflammation
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Paneni, F., Costantino, S., Castello, L., Battista, R., Capretti, G., Chiandotto, S., ... Cosentino, F. (2015). Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: Insights in patients with diabetes. European Heart Journal, 36(13), 817-828. https://doi.org/10.1093/eurheartj/ehu179

Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction : Insights in patients with diabetes. / Paneni, Francesco; Costantino, Sarah; Castello, Lorenzo; Battista, Rodolfo; Capretti, Giuliana; Chiandotto, Sergio; D'Amario, Domenico; Scavone, Giuseppe; Villano, Angelo; Rustighi, Alessandra; Crea, Filippo; Pitocco, Dario; Lanza, Gaetano; Volpe, Massimo; Del Sal, Giannino; Lüscher, Thomas F.; Cosentino, Francesco.

In: European Heart Journal, Vol. 36, No. 13, 01.04.2015, p. 817-828.

Research output: Contribution to journalArticle

Paneni, F, Costantino, S, Castello, L, Battista, R, Capretti, G, Chiandotto, S, D'Amario, D, Scavone, G, Villano, A, Rustighi, A, Crea, F, Pitocco, D, Lanza, G, Volpe, M, Del Sal, G, Lüscher, TF & Cosentino, F 2015, 'Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: Insights in patients with diabetes', European Heart Journal, vol. 36, no. 13, pp. 817-828. https://doi.org/10.1093/eurheartj/ehu179
Paneni, Francesco ; Costantino, Sarah ; Castello, Lorenzo ; Battista, Rodolfo ; Capretti, Giuliana ; Chiandotto, Sergio ; D'Amario, Domenico ; Scavone, Giuseppe ; Villano, Angelo ; Rustighi, Alessandra ; Crea, Filippo ; Pitocco, Dario ; Lanza, Gaetano ; Volpe, Massimo ; Del Sal, Giannino ; Lüscher, Thomas F. ; Cosentino, Francesco. / Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction : Insights in patients with diabetes. In: European Heart Journal. 2015 ; Vol. 36, No. 13. pp. 817-828.
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AU - Chiandotto, Sergio

AU - D'Amario, Domenico

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