title: Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Cardiology 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paneni
authors.affiliation: Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden.
authors.forename: Sarah
authors.initials: S
authors.lastname: Costantino
authors.affiliation: Cardiology, Department of Clinical and Molecular Medicine, University of Rome 'Sapienza', Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Castello
authors.affiliation: Internal Medicine Unit, Civil Hospital, Sora, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Battista
authors.affiliation: Cardiology, Department of Clinical and Molecular Medicine, University of Rome 'Sapienza', Rome, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Capretti
authors.affiliation: Cardiology, Department of Clinical and Molecular Medicine, University of Rome 'Sapienza', Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Chiandotto
authors.affiliation: Department of Cardiovascular Medicine, Catholic University, Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Amario
authors.affiliation: Diabetes Care Unit, Internal Medicine, Catholic University, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scavone
authors.affiliation: Department of Cardiovascular Medicine, Catholic University, Rome, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Villano
authors.affiliation: Laboratorio Nazionale CIB, AREA Science Park and Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rustighi
authors.affiliation: Department of Cardiovascular Medicine, Catholic University, Rome, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
authors.affiliation: Diabetes Care Unit, Internal Medicine, Catholic University, Rome, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Pitocco
authors.affiliation: Department of Cardiovascular Medicine, Catholic University, Rome, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Lanza
authors.affiliation: IRCCS Neuromed, Pozzilli, Italy Cardiology, Department of Clinical and Molecular Medicine, University of Rome 'Sapienza', Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Volpe
authors.affiliation: Laboratorio Nazionale CIB, AREA Science Park and Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.affiliation: Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: Cardiology 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cosentino
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D045304:Cytochromes c / Q000096:biosynthesis; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D028361:Mitochondrial Diseases / Q000517:prevention & control*; D016328:NF-kappa B / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015854:Up-Regulation / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014657:Vasculitis / Q000503:physiopathology
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D017382:Reactive Oxygen Species; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D045304:Cytochromes c; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D005947:Glucose
keywords: Diabetes mellitus; Endothelial function; Inflammation; Oxidative stress