期刊
EUROPEAN HEART JOURNAL
卷 36, 期 13, 页码 817-828出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehu179
关键词
Oxidative stress; Endothelial function; Inflammation; Diabetes mellitus
资金
- Swiss Heart Foundation
- Italian Ministry of Education, University and Research
- PRIN
- Swiss National Research Foundation [3100-06811802/1]
- PhD programme in Experimental Medicine at the University of Rome 'Sapienza'
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
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-kappa B 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-kappa B 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 F-2 alpha and plasma levels of adhesion molecules. Conclusions Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kappa B-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes.
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