interleukin-8 and Diabetic-Cardiomyopathies

Interleukin (IL)-8 is a proinflammatory C-X-C chemokine involved in inflammation underling cardiac diseases, primary or in comorbid condition, such diabetic cardiomyopathy (DCM). The phosphodiesterase type 5 inhibitor sildenafil can ameliorate cardiac conditions by counteracting inflammation. The study aim is to evaluate the effect of sildenafil on serum IL-8 in DCM subjects vs. placebo, and on IL-8 release in human endothelial cells (Hfaec) and peripheral blood mononuclear cells (PBMC) under inflammatory stimuli.. IL-8 was quantified: in sera of (30) DCM subjects before (baseline) and after sildenafil (100 mg/day, 3-months) vs. (16) placebo and (15) healthy subjects, by multiplatform array; in supernatants from inflammation-challenged cells after sildenafil (1 µM), by ELISA.. Baseline IL-8 was higher in DCM vs. healthy subjects (149.14 ± 46.89 vs. 16.17 ± 5.38 pg/ml, p < 0.01). Sildenafil, not placebo, significantly reduced serum IL-8 (23.7 ± 5.9 pg/ml, p < 0.05 vs. baseline). Receiver operating characteristic (ROC) curve for IL-8 was 0.945 (95% confidence interval of 0.772 to 1.0, p < 0.01), showing good capacity of discriminating the response in terms of drug-induced IL-8 decrease (sensitivity of 0.93, specificity of 0.90). Sildenafil significantly decreased IL-8 protein release by inflammation-induced Hfaec and PBMC and downregulated IL-8 mRNA in PBMC, without affecting cell number or PDE5 expression.. Sildenafil might be suggested as potential novel pharmacological tool to control DCM progression through IL-8 targeting at systemic and cellular level.

Topics: Case-Control Studies; Cell Proliferation; Cells, Cultured; Diabetic Cardiomyopathies; Female; Follow-Up Studies; Humans; In Vitro Techniques; Inflammation Mediators; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prognosis; Sildenafil Citrate

The C-X-C motif chemokine ligand 10 (CXCL10) participates in diabetes and diabetic cardiomyopathy development from the early stages. Rosiglitazone (RGZ) exhibits anti-inflammatory properties and can target cardiomyocytes secreting CXCL10, under interferon (IFN)γ and tumor necrosis factor (TNF)α challenge. Cardiomyocyte remodeling, CD4 + T cells and dendritic cells (DCs) significantly contribute to the inflammatory milieu underlying and promoting disease development. We aimed to study the effect of RGZ onto inflammation-induced secretion of CXCL10, IFNγ, TNFα, interleukin (IL)-6 and IL-8 by human CD4 + T and DCs, and onto IFNγ/TNFα-dependent signaling in human cardiomyocytes associated with chemokine release.. Cells maintained within an inflammatory-like microenvironment were exposed to RGZ at near therapy dose (5 µM). ELISA quantified cytokine secretion; qPCR measured mRNA expression; Western blot analyzed protein expression and activation; immunofluorescent analysis detected intracellular IFNγ/TNFα-dependent trafficking.. In human CD4 + T cells and DCs, RGZ inhibited CXCL10 release likely with a transcriptional mechanism, and reduced TNFα only in CD4 + T cells. In human cardiomyocytes, RGZ impaired IFNγ/TNFα signal transduction, blocking the phosphorylation/nuclear translocation of signal transducer and activator of transcription 1 (Stat1) and nuclear factor-kB (NF-kB), in association with a significant decrease in CXCL10 expression, IL-6 and IL-8 release.. As the combination of Th1 biomarkers like CXCL10, IL-8, IL-6 with classical cardiovascular risk factors seems to improve the accuracy in predicting T2D and coronary events, future studies might be desirable to further investigate the anti-Th1 effect of RGZ.

Topics: Anti-Inflammatory Agents; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Humans; Hypoglycemic Agents; Inflammation; Interferon-gamma; Interleukin-8; Myocytes, Cardiac; NF-kappa B; Prognosis; Rosiglitazone; T-Lymphocytes, Helper-Inducer; Thiazolidinediones; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the protective effect of 5-HMF on human umbilical vein endothelial cells (HUVECs) injured by high glucose in vitro, and the mechanism underlying this process. Our results demonstrated that high glucose-induced oxidative stress in HUVECs was mainly mediated through activation of reactive oxygen species (ROS), Jun N-kinase 2/3 (JNK2/3) and plasma interleukin-8 (IL-8), and inactivation of phosphorylated protein kinase B (P-Akt). Treatment of HUVECs with media containing high glucose (4.5%) in the presence of 5-HMF (100, 200 and 400 μM) resulted in significant inhibition of high glucose-induced oxidative stress and expression of JNK1 and JNK2/3. Furthermore, 5-HMF rapidly inhibited high glucose-induced activation of IL-8, a downstream activator of P-Akt. Diabetes mellitus can cause a wide variety of vascular complications and high glucose can induce vascular endothelial cell apoptosis. Free radicals are formed disproportionately in diabetes by glucose oxidation. The finding of this study highlights the pharmacological application of 5-HMF for preventing cardiovascular and diabetes mellitus diseases, and provides the theoretical basis for further development of a Cornus officinalis agent for diabetes-associated vascular diseases.

Topics: Apoptosis; Cornus; Diabetic Cardiomyopathies; Furaldehyde; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Oxidative Stress; Plant Extracts; Reactive Oxygen Species