Edited by Laszlo NagyKeywords: MicroRNA Macrophage Lipoprotein Toll-like receptor 4 Atherosclerosis a b s t r a c t Atherosclerosis is an inflammatory process due to oxidized low-density lipoprotein (oxLDL) accumulation in macrophages. We investigated the involvement of microRNAs in oxLDL accumulation and inflammatory response in macrophages. The expression of miR-146a decreases under oxLDL stimulation. MiR-146a significantly reduces intracellular LDL cholesterol content and secretion of interleukin 6, interleukin 8, chemokine (C-C motif) ligand 2 and matrix metallopeptidase 9. Toll-like receptor 4 (TLR4) is a relevant target of miR-146a, and miR-146a inhibits the activation of TLR4-dependent intracellular signaling pathways involved in cytoskeleton rearrangement, lipid uptake, and inflammatory cytokine secretion. These results indicate that miR-146a contributes to the regulation of both oxLDL accumulation and inflammatory response by negatively regulating TLR4 and thereby inhibiting the activation of TLR4-dependent signaling pathways. Over-expression of miR146a may be useful in the prevention and treatment of atherosclerosis.

Supplementary data are available at Bioinformatics online.

Background: Macrophage-associated immune response plays an important role in myocardial ischemia/reperfusion (IR) injury. Dectin-1, expressed mainly on activated myeloid cells, is crucial for the regulation of immune homeostasis as a pattern recognition receptor. However, its effects and roles during the myocardial IR injury remain unknown. Methods: Genetic ablation, antibody blockade, or Dectin-1 activation, along with the adoptive bone marrow transfer chimeric model, was used to determine the functional significance of Dectin-1 in myocardial IR injury. Immune cell filtration and inflammation were examined by flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Moreover, Dectin-1 + cells were analyzed by flow cytometry in the blood of patients with ST-segment–elevation myocardial infarction and stable patients with normal coronary artery (control). Results: We demonstrated that Dectin-1 expression observed on the bone marrow–derived macrophages is increased in the heart during the early phase after IR injury. Dectin-1 deficiency and antibody-mediated Dectin-1 inhibition led to a considerable improvement in cardiac function, accompanied by a reduction in cardiomyocyte apoptosis, which was associated with a decrease in M1 macrophage polarization and Ly-6C + monocyte and neutrophil infiltration. Activation of Dectin-1 with its agonist had the opposite effects. Furthermore, Dectin-1 contributed to neutrophil recruitment through the regulation of Cxcl1 and granulocyte colony-stimulating factor expression. In addition, Dectin-1–dependent interleukin-23/interleukin-1β production was shown to be essential for interleukin-17A expression by γδT cells, leading to neutrophil recruitment and myocardial IR injury. Furthermore, we demonstrated that circulating Dectin-1 + CD14 ++ CD16 − and Dectin-1 + CD14 ++ CD16 + monocyte levels were significantly higher in patients with ST-segment–elevation myocardial infarction than in controls and positively correlated with the severity of cardiac dysfunction. Conclusions: Our results reveal a crucial role of Dectin-1 in the process of mouse myocardial IR injury and provide a new, clinically significant therapeutic target.

BackgroundProkineticin-2 is confirmed to be involved in the inflammatory process. Inflammation plays an important role in the pathogenesis of metabolic syndrome (MS). However, whether prokineticin-2 is associated with MS or not remains unknown. Thus, we present this study to explore the association between prokineticin-2 and MS in a Chinese population.MethodsThis study included 162 middle-aged and elderly Chinese patients with cardiovascular risk factors. The relationship between serum prokineticin-2 levels and various cardiometabolic risk factors, and MS were evaluated.ResultsThe participants with serum prokineticin-2 levels >6.32 ng/ml had increased waist circumference, body mass index (BMI), plasma triglyceride, diastolic blood pressure (DBP), blood glucose, and serum uric acid, but decreased age, plasma high-density lipoprotein cholesterol (HDL-C), and HDL-C/total cholesterol (TC) (all P < 0.05). A higher percentage of them had history of lipid disorders (19.3 vs 2.5 %, P = 0.001) and MS (77.1 vs 48.1 %, P < 0.001). Prokineticin-2 was positively correlated with TC (partial correlation coefficient: 0.233, P = 0.011), triglyceride (partial correlation coefficient: 0.504, P < 0.001), fasting plasma glucose (partial correlation coefficient: 0.336, P < 0.001), HbA1c (partial correlation coefficient: 0.285, P = 0.002), and uric acid (partial correlation coefficient: 0.234, P = 0.011) respectively, but was negatively correlated with HDL-C/TC (partial correlation coefficient: −0.269, P = 0.003) with adjustment for age, man, and BMI. Prokineticin-2 was significantly elevated in participants with MS (7.72 ± 3.34 vs 5.56 ± 2.39 ng/ml, P < 0.001). Furthermore, prokineticin-2 was significantly elevated in participants with increased numbers of MS components (5.17 ± 2.29 vs 5.94 ± 2.47 vs 7.13 ± 3.33 vs 8.32 ± 2.81 vs 9.82 ± 4.37 ng/ml, P for trend <0.001). Multiple logistic regression analysis indicated that prokineticin-2 was independently associated with MS (OR: 1.307, 95 % confidence interval: 1.127–1.515, P < 0.001) with adjustment for other potential confounders. If serum prokineticin-2 value can be considered as an indicator to discriminate MS, receiver operating characteristic curve analysis exhibited the area under the curve as 0.701.ConclusionsProkineticin-2 is correlated with various cardiometabolic risk factors including blood lipid, blood glucose, blood pressure, BMI, and uric acid. And furthermore, the increased prokineticin-2 is independently associated with MS.

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BackgroundCardiovascular disease is the leading cause of death in patients with chronic kidney disease. A body of evidence suggests that p-cresyl sulfate (PCS), a uremic toxin, is associated with the cardiovascular mortality rate of patients with chronic kidney disease; however, the molecular mechanisms underlying this feature have not yet been fully elucidated.Methods and ResultsWe aimed to determine whether PCS accumulation could adversely affect cardiac dysfunction via direct cytotoxicity to cardiomyocytes. In mice that underwent 5/6 nephrectomy, PCS promoted cardiac apoptosis and affected the ratio of left ventricular transmitral early peak flow velocity to left ventricular transmitral late peak flow velocity (the E/A ratio) observed by echocardiography (n=8 in each group). Apocynin, an inhibitor of NADPH oxidase activity, attenuates this alteration of the E/A ratio (n=6 in each group). PCS also exhibited proapoptotic properties in H9c2 cells by upregulating the expression of p22phox and p47phox, NADPH oxidase subunits, and the production of reactive oxygen species. Apocynin and N-acetylcysteine were both able to suppress the effect of PCS, underscoring the importance of NADPH oxidase activation for the mechanism of action.ConclusionsThis study demonstrated that the cardiac toxicity of PCS is at least partially attributed to induced NADPH oxidase activity and reactive oxygen species production facilitating cardiac apoptosis and resulting in diastolic dysfunction.

BackgroundThe extent of coronary collateral formation is a primary determinant of the severity of myocardial damage and mortality after coronary artery occlusion. Type 2 diabetes mellitus (T2DM) represents an important risk factor for impaired collateral vessel growth. However, the mechanism of reduced coronary collateralization in type 2 diabetic patients remains unclear.MethodsWith the reference to the recent researches, this review article describes the pathogenic effects of T2DM on collateral development and outlines possible clinical and biochemical markers associated with reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion (CTO).ResultsDiffuse coronary atherosclerosis in T2DM reduces pressure gradient between collateral donor artery and collateral recipient one, limiting collateral vessel growth and function. An interaction between advanced glycation end-products and their receptor activates several intracellular signaling pathways, enhances oxidative stress and aggravates inflammatory process. Diabetic condition decreases pro-angiogenic factors especially vascular endothelial growth factor and other collateral vessel growth related parameters. Numerous clinical and biochemical factors that could possibly attenuate the development of coronary collaterals have been reported. Increased serum levels of glycated albumin, cystatin C, and adipokine C1q tumor necrosis factor related protein 1 were associated with poor coronary collateralization in type 2 diabetic patients with stable coronary artery disease and CTO. Diastolic blood pressure and stenosis severity of the predominant collateral donor artery also play a role in coronary collateral formation.ConclusionsT2DM impairs collateral vessel growth through multiple mechanisms involving arteriogenesis and angiogenesis, and coronary collateral formation in patients with T2DM and CTO is influenced by various clinical, biochemical and angiographic factors. This information provides insights into the understanding of coronary pathophysiology and searching for potential new therapeutic targets in T2DM.

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