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Aims Smokers are at increased risk of cardiovascular events. However, the exact mechanisms through which smoking influences cardiovascular disease resulting in accelerated atherosclerosis and vascular calcification are unknown. The aim of this study was to investigate effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification and to elucidate underlying mechanisms. Methods and results We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (µCT) scanning. Calcification was present more often in carotid plaques of smokers (n = 22 of 30, 73.3%) compared to non-smokers (n = 11 of 32, 34.3%; P Conclusion In this study, we provide evidence that nicotine induces Nox5-mediated pro-calcific processes as novel mechanism of increased atherosclerotic calcification. We identified that activation of α7 and α3 nAChR by nicotine increases intracellular Ca2+ and initiates calcification of hVSMCs through increased Nox5 activity, leading to oxidative stress-mediated EV release. Identifying the role of Nox5-induced oxidative stress opens novel avenues for diagnosis and treatment of smoking-induced cardiovascular disease.

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose–mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose–induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.

Aims: Transition metal ions have been implicated in atherosclerosis. The goal of this study was to investigate whether metal ion levels were higher in people with diabetes, in view of their increased risk of aggravated atherosclerosis. Methods and results: Absolute concentrations of iron, copper, zinc and calcium, and products of protein and lipid oxidation were quantified in atherosclerotic lesions from subjects with (T2DM, n = 27), without Type 2 diabetes (nonDM, n = 22), or hyperglycaemia (HG, n = 17). Iron (P

Background. Circulating progenitor cells (PC) can positively influence the healing of ischaemic myocardium. Cardiovascular risk factors including diabetes mellitus (DM) may have a negative influence on both number and recruitment of PC. Recent evidence suggests that less differentiated CD133+PC contribute to myocardial healing and are promising candidates for therapy. Therefore, we investigated whether DM affects CD133+PC. Methods. CD133+PC were analyzed in patients following acute myocardial infarction and successful reperfusion [acute myocardial infarction (AMI, n = 45) with/without non-insulin-requiring type 2 DM (T2DM)]. Stable coronary artery disease patients (CAD, n = 45) served as stable controls. Number and phenotype of CD133+PC were assessed by flow cytometry. CD133+PC chemotaxis was assessed towards vascular endothelial growth factor, an angiogenic stimulus upregulated in AMI. The expression of anti-oxidant enzymes in CD133+PC was detected by reverse-transcriptase PCR. Results. In non-DM patients, the number of CD133+PC increased on day 3 following AMI (P = 0.0001). In contrast, no changes were observed in AMI patients with T2DM. Regarding the function of CD133+PC, an enhanced chemotactic response was observed following AMI in both non-DM (P = 0.0001) and T2DM (P = 0.007). However, the AMI-related functional activation was significantly weaker in diabetic patients (P = 0.001). Moreover, the expression of catalase was lower in CD133+PC from T2DM. Conclusions. Our results show that T2DM not only limits the abundance of CD133+PC following AMI, but also limits their activation. This might be explained by a lower resistance of CD133+PC to oxidative stress. Our data provide a possible explanation for the delayed postischaemic vascular healing and myocardial recovery in DM.

Objective— The role of antioxidants in preventing vascular disease remains controversial. Vascular endothelial growth factor (VEGF-A) is important for endothelial and monocyte function. This study investigated the negative effects of smoking on monocyte migratory responsiveness to VEGF-A and the usefulness of vitamin C to prevent smoking-induced monocyte dysfunction. Methods and Results— The chemotactic response of isolated monocytes from a cohort of 17 non-smokers and 10 smokers toward VEGF-A was assessed. VEGF-A significantly stimulated the migration of monocytes in non-smokers; the monocytes from smokers failed to respond to VEGF-A. Repeated analysis after 2 weeks of vitamin C intake (2g/d) showed a fully restored VEGF-A-induced monocyte migration in smokers. VEGF-A serum levels were not altered by vitamin C. VEGF-A-inducible kinase activity was intact in monocytes from smokers as assessed by in vitro kinase assay. Monocyte dysfunction can be mimicked in vitro by challenging monocytes with a range of reactive oxygen species (ROS). Conclusions— Stimulation of monocyte migration by VEGF-A was severely attenuated in smokers, and the deficit observed was surmounted by vitamin C supplementation. The negative effects of smoking on monocyte function may translate into adverse impacts on VEGF-A-dependent repair processes such as arteriogenesis. These results propose a causative role of oxidative stress in smoking-induced monocyte dysfunction.