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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.)

Aims: We aimed to compare coronary artery disease (CAD) at the time of a first acute coronary syndrome (ACS) in type II diabetic and non-diabetic patients by coronary angiography and by optical coherence tomography (OCT)., Methods and Results: Two different patient populations with a first ACS were enrolled for the angiographic (167 patients) and the OCT (72 patients) substudy. Angiographic CAD severity was assessed by Bogaty, Gensini, and Sullivan scores, whereas collateral development towards the culprit vessel was assessed by the Rentrop score. Optical coherence tomography plaque features were evaluated at the site of the minimum lumen area (MLA) and of culprit segment. In the angiographic substudy, at multivariate analysis, diabetes was associated with both the stenosis score and the extent index (P = 0.001). Furthermore, well-developed collateral circulation (Rentrop 2-3) towards the culprit vessel was more frequent in diabetic than in non-diabetic patients (73% vs. 16%, P = 0.001). In the OCT substudy, at MLA site lipid quadrants were less and the lipid arc was smaller in diabetic than in non-diabetic patients (2.3 ± 1.3 vs. 3.0 ± 1.2; P = 0.03 and 198° ± 121° vs. 260° ± 118°; P = 0.03). Furthermore, the most calcified cross-section along the culprit segment had a greater number of calcified quadrants and a wider calcified arc in diabetic than in non-diabetic patients (1.7 ± 1.0 vs. 1.2 ± 0.9; P = 0.03 and 126° ± 95° vs. 81° ± 80°; P = 0.03). Superficial calcified nodules were more frequently found in diabetic than in non-diabetic patients (79 vs. 54%, P = 0.04)., Conclusions: In spite of potent pro-inflammatory, pro-oxidant and pro-thrombotic stimuli operating in type II diabetes, diabetic patients exhibit substantially more severe coronary atherosclerosis than non-diabetic patients at the time of a first acute coronary event. Better collateral development towards the culprit vessel, a predominantly calcific plaque phenotype and, probably, yet unknown protective factors operating in diabetic patients may explain these intriguing paradoxical findings.

Aims: Diabetes mellitus (DM) is associated with high incidence of first and recurrent cardiovascular events, especially acute coronary syndromes (ACSs); however, the mechanisms involved are still unknown. We sought to investigate the role of CD4(+)CD28(null)T-lymphocytes, a rare long-lived subset of T-lymphocytes with proatherogenic and plaque-destabilizing properties, in the increased cardiovascular risk associated with DM., Methods and Results: CD4(+)CD28(null)T-cell frequency was analysed by flow-cytometry in 60 DM patients without overt cardiovascular disease (cDM), in 166 ACS patients with or without DM (ACS/DM+, n= 51 and ACS/DM-, n= 115), and in 60 healthy individuals. The incidence of cardiovascular events (death, myocardial infarction, unstable angina) was assessed at 36 months follow-up. CD4+CD28(null)T-cell frequency (median, range) was higher in ACS/DM+ (12.7%, 0.1-48) vs. ACS/DM- (3.9%, 0.2-35), cDM (3.1%, 0.3-22.4), and controls (1.5%, 0.1-9.1) (P< 0.001 for all comparisons). Notably, cDM patients had significantly higher CD4+CD28(null)T-cell frequency than controls (P= 0.001). Glycosylated haemoglobin A(1c) was the only parameter independently associated with CD4+CD28(null)T-cells in cDM. The 36-month event-free survival was significantly lower in cDM patients with CD4+CD28(null)T-cells ≥4% (90th percentile of normal distribution) than in those with CD4+CD28(null)T-cells <4% (P= 0.039). Among ACS patients, the 36-month event-free survival was the lowest in those with DM and CD4+CD28(null)T-cells ≥4% and highest in those without DM and CD4+CD28(null)T-cells <4% (P< 0.001), being intermediate in those with only one of these features., Conclusions: In DM patients, CD4+CD28(null)T-cells are expanded and are associated with poor glycaemic control; they also correlate with the occurrence of a first cardiovascular event and with a worse outcome after an ACS.

Aims: Although aspirin treatment is useful in reducing ischaemic events in diabetic patients, recent studies suggest that it is less effective when compared with non-diabetics (ND). We sought to evaluate COX-1 sensitivity and thromboxane A(2) (TxA(2)) production in type 1 (T1DM) and type 2 diabetic (T2DM) patients under chronic aspirin treatment, and also evaluate the association between thromboxane A(2) (TxA(2)) production and markers of inflammation and metabolic control, such as high-sensitivity C-reactive protein, fasting blood glucose, and haemoglobin A1c (HbA1c)., Methods and Results: Agonist-induced platelet aggregation (PA) and TxB(2), a stable metabolite of TxA(2), production, serum TxB(2), and platelet COX-1 and COX-2 expression were studied in T2DM patients, T1DM patients, and high-risk ND subjects, all receiving a low dose of aspirin. TxB(2) formation was studied in platelets treated in vitro with aspirin alone or with a COX-2 inhibitor (NS-398). PA, collagen-induced TxB(2) production, and serum TxB(2) were higher in T1DM and T2DM patients than in ND subjects. TxB(2) production was reduced in diabetic patients by in vitro treatment with aspirin. COX-2 was expressed in all diabetic patients but only in 46% of ND patients. In diabetic patients significant correlations were observed between TxB(2) production and both fasting plasma glucose and HbA1c., Conclusion: COX-1 sensitivity and TxB(2) production is similarly reduced in both T1DM and T2DM patients under chronic aspirin treatment. The association between TxB(2) production and either fasting plasma glucose and HbA1c levels suggests that in diabetic patients hyperglycaemia is a determinant of the reduced platelet sensitivity to aspirin.

Aims: To assess the relationship between cardiac autonomic dysfunction and inflammation in patients with type 1 diabetes and whether beta-blocker therapy might improve both abnormalities in these patients., Methods and Results: We studied 49 patients with type 1 diabetes (age 50.5 +/- 11 years, 33 men). Serum levels of high-sensitivity C-reactive protein, as a marker of inflammation, and frequency-domain heart rate variability (HRV) on 24 h Holter monitoring, as a measure of cardiac autonomic function, were assessed in all patients. Twenty-one patients with depressed HRV were subsequently randomized to receive atenolol (50 mg daily) or no-beta-blockade. HRV and C-reactive protein were re-assessed after 3-4 weeks from randomization. An inverse correlation was found between C-reactive protein levels and HRV parameters, with the highest r coefficient shown with low-frequency (LF) power (r = -0.38; P = 0.007). Furthermore, C-reactive protein serum levels were significantly higher in patients with bottom quartile values of LF power compared with patients with values in the three top quartiles (4.64 +/- 2.8 vs.1.79 +/- 1.6 mg/L, respectively; P = 0.003), also after adjustment for potential confounding variables (P = 0.013). HRV parameters improved significantly in patients treated with atenolol, but not in the no-atenolol group. Furthermore, C-reactive protein levels decreased in the beta-blockade group, but not in the no-beta-blockade group (P = 0.04 for changes between groups)., Conclusion: In type 1 diabetic patients, serum C-reactive protein levels are significantly associated with depressed HRV; the favourable effects of beta-blockade on both HRV parameters and C-reactive protein serum levels suggest that autonomic nervous system may have significant modulator effects on inflammation.