Background-We hypothesized that the inflammatory cytokine tumor necrosis factor-␣ (TNF) produces endothelial dysfunction in type 2 diabetes. Methods and Results-In m Leprdb control mice, sodium nitroprusside and acetylcholine induced dose-dependent vasodilation, and dilation to acetylcholine was blocked by the NO synthase inhibitor N G -monomethyl-L-arginine. In type 2 diabetic (Lepr db ) mice, acetylcholine-or flow-induced dilation was blunted compared with m Lepr db , but sodium nitroprusside produced comparable dilation. In Lepr db mice null for TNF (db TNFϪ /db TNFϪ ), dilation to acetylcholine or flow was greater than in diabetic Lepr db mice and comparable to that in controls. Plasma concentration of TNF was significantly increased in Lepr db versus m Lepr db mice. Real-time polymerase chain reaction and Western blotting showed that mRNA and protein expression of TNF and nuclear factor-B were higher in Lepr db mice than in controls. Administration of anti-TNF or soluble receptor of advanced glycation end products attenuated nuclear factor-B and TNF expression in the Lepr db mice. Immunostaining results show that TNF in mouse heart is localized predominantly in vascular smooth muscle cells rather than in endothelial cells and macrophages. Superoxide generation was elevated in vessels from Lepr db mice versus controls. Administration of the superoxide scavenger TEMPOL, NAD(P)H oxidase inhibitor (apocynin), or anti-TNF restored endothelium-dependent dilation in Lepr db mice. NAD(P)H oxidase activity, protein expression of nitrotyrosine, and hydrogen peroxide production were increased in Lepr db mice (compared with controls), but these variables were restored to control levels by anti-TNF. Conclusion-Advanced glycation end products/receptor of advanced glycation end products and nuclear factor-B signaling play pivotal roles in TNF expression through an increase in circulating and/or local vascular TNF production in the Lepr db mouse with type 2 diabetes. Increases in TNF expression induce activation of NAD(P)H oxidase and production of reactive oxidative species, leading to endothelial dysfunction in type 2 diabetes. (Circulation. 2007;115: 245-254.)

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A reduction in hospital admissions for acute coronary syndromes (ACS) has been observed globally in the aftermath of the pneumonia outbreak caused by coronavirus disease 2019 . 1 Despite emergence of anecdotal reports, formal evaluation of variation in percutaneous coronary intervention (PCI) rates during the COVID-19 outbreak has not yet been reported. Italy is one of the countries most heavily affected by the COVID-19 pandemic with 168,941 confirmed cases and 22,170 deaths as of April 5, 2020.We investigated the association between the outbreak of COVID-19 and PCI rates for ACS in the Campania region, which with 5.8 million residents represents about 10% of the Italian population. Data were obtained from 20 out of 21 PCI centers over an 8-week period, including 4-week before and 4-week after the COVID-19 outbreak corresponding with the first reported case declared by the Civil Protection Department on February 27, 2020. Incidence rates and their ratios were calculated using Poisson regression analysis and interactions for gender and age were estimated by adding the interaction term to the regression models. 2 Population denominators, which were used as offset, were obtained from the Italian census. The ratio change in PCI rates for the entire 8-week interval was estimated by adding a linear term to the Poisson regression. The study was approved by the Ethics Committee of the University of Naples Federico II (Naples, Italy).From January 30, 2020 to March 26, 2020, a total of 1,831 PCIs were performed in the Campania region; of them 738 (40.31%) were elective PCI (not included), 604 (32.99%) PCI for non-ST-segment elevation acute ACS (NSTE-ACS), and 489 (26.71%) PCI for ST-segment elevation myocardial infarction (STEMI). Mean age was 65.7 years (standard deviation 12), and 804/1,093 PCIs (73.56%) were performed in men. There were no differences in mean age

Endothelium-derived hyperpolarizing factor (EDHF) plays a crucial role in modulating vasomotor tone, especially in microvessels when nitric oxide-dependent control is compromised such as in diabetes. Epoxyeicosatrienoic acids (EETs), potassium ions (K+), and hydrogen peroxide (H2O2) are proposed as EDHFs. However, the identity (or identities) of EDHF-dependent endothelial dilators has not been clearly elucidated in diabetes. We assessed the mechanisms of EDHF-induced vasodilation in wild-type (WT, normal), db/db (advanced type 2 diabetic) mice, and db/db mice null for TNF (dbTNF-/dbTNF-). In db/db mice, EDHF-induced vasodilation [ACh-induced vasodilation in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME, 10 micromol/l) and prostaglandin synthase inhibitor indomethacin (Indo, 10 mumol/l)] was diminished after the administration of catalase (an enzyme that selectively dismutates H2O2 to water and oxygen, 1,000 U/ml); administration of the combination of charybdotoxin (a nonselective blocker of intermediate-conductance Ca2+-activated K+ channels, 10 micromol/l) and apamin (a selective blocker of small-conductance Ca2+-activated K+ channels, 50 micromol/l) also attenuated EDHF-induced vasodilation, but the inhibition of EETs synthesis [14,15-epoxyeicosa-5(Z)-enoic acid; 10 mumol/l] did not alter EDHF-induced vasodilation. In WT controls, EDHF-dependent vasodilation was significantly diminished after an inhibition of K+ channel, EETs synthesis, or H2O2 production. Our molecular results indicate that mRNA and protein expression of interleukin-6 (IL-6) were greater in db/db versus WT and dbTNF-/dbTNF- mice, but neutralizing antibody to IL-6 (anti-IL-6; 0.28 mg.ml(-1).kg(-1) ip for 3 days) attenuated IL-6 expression in db/db mice. The incubation of the microvessels with IL-6 (5 ng/ml) induced endothelial dysfunction in the presence of l-NAME and Indo in WT mice, but anti-IL-6 restored ACh-induced vasodilation in the presence of L-NAME and Indo in db/db mice. In db(TNF-)/db(TNF-) mice, EDHF-induced vasodilation was greater and comparable with controls, but IL-6 decreased EDHF-mediated vasodilation. Our results indicate that EDHF compensates for diminished NO-dependent dilation in IL-6-induced endothelial dysfunction by the activation of H2O2 or a K+ channel in type 2 diabetes.

The exploration of coronary microcirculatory dysfunction in diabetes has accelerated in recent years. Cardiac function is compromised in diabetes. Diabetic patients manifest accelerated atherosclerosis in coronary arteries. These data are confirmed in diabetic animal models, where lesions of small coronary arteries have been described. These concepts are epitomized in the classic microvascular complications of diabetes, i.e. blindness, kidney failure and distal dry gangrene. Most importantly, accumulating data indicate that insights gained from the link between inflammation and diabetes can yield predictive and prognostic information of considerable clinical utility. This review summarizes the evidence for the predisposing factors and the mechanisms involved in diabetes, and assesses the current state of knowledge regarding the triggers for inflammation in this disease. We evaluate the roles of hyperglycemia, oxidative stress, polyol pathway, protein kinase C, advanced glycation end products, insulin resistance, peroxisome proliferator-activated receptor-γ, inflammation, and diabetic cardiomyopathy as a "stem cell disease". Furthermore, we discuss the mechanisms responsible for impaired coronary arteriole function. Finally, we consider how new insights in diabetes may provide innovative therapeutic strategies.