RESUMO
BACKGROUND: Obesity is related to coronary artery disease (CAD) and worse outcomes in coronary artery bypass graft (CABG) patients. Adipose tissue itself is an endocrine organ that secretes many humoral mediators, such as adipokines, which can induce or reduce inflammation and oxidative stress. OBJECTIVES: We investigate the relationship between the body mass index (BMI), inflammation, and oxidative stress by measuring serum levels of leptin, interleukin-6, and 3-nitrotyrosine in CABG patients and correlate their levels to the cardiovascular and operative risk profiles. METHODS AND RESULTS: 45 men (<75 years) with a median BMI of 29 (21-51) kg/m2, who were diagnosed with CAD and scheduled for elective CABG, were included after applying the following exclusion criteria: prior myocardial infarction, reoperation, female gender, and smoking. Patients' blood samples were taken preoperatively. Several markers were measured. We found significant correlations between leptin and BMI (p < 0.0001) as well as between leptin and 3-nitrotyrosine (p = 0.006). Interleukin-6 was correlated with C-reactive protein (p < 0.0001) and with the incidence of insulin-dependent diabetes mellitus (p = 0.036), arterial hypertension (p = 0.044), reduced left ventricular function (p = 0.003), and severe coronary calcification (p = 0.015). It was also associated with significantly longer extracorporeal bypass time (p = 0.009). Postoperative deep sternal wound infections could be predicted by a higher BMI (p = 0.003) and leptin level (p = 0.001). CONCLUSIONS: There seems to be a correlation between inflammatory processes and cardiovascular morbidity in our cohort. Further, the incidence of deep sternal wound infections is related to a higher BMI and leptin serum level.
Assuntos
Ponte de Artéria Coronária/efeitos adversos , Doença da Artéria Coronariana/fisiopatologia , Inflamação/metabolismo , Leptina/metabolismo , Idoso , Índice de Massa Corporal , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The anthracycline doxorubicin (DOX) is widely used in cancer therapy with the limitation of cardiotoxicity leading to the development of congestive heart failure. DOX-induced oxidative stress and changes of the phosphoproteome as well as epigenome were described but the exact mechanisms of the adverse long-term effects are still elusive. Here, we tested the impact of DOX treatment on cell death, oxidative stress parameters and expression profiles of proteins involved in epigenetic pathways in a cardiomyocyte cell culture model. Markers of oxidative stress, apoptosis and expression of proteins involved in epigenetic processes were assessed by immunoblotting in cultured rat myoblasts (H9c2) upon treatment with DOX (1 or 5⯵M for 24 or 48â¯h) in adherent viable and detached apoptotic cells. The apoptosis markers cleaved caspase-3 and fractin as well as oxidative stress markers 3-nitrotyrosine and malondialdehyde were dose-dependently increased by DOX treatment. Histone deacetylases (SIRT1 and HDAC2), histone lysine demethylases (KDM3A and LSD1) and histone lysine methyltransferases (SET7 and SMYD1) were significantly regulated by DOX treatment with generation of cleaved protein fragments and posttranslational modifications. Overall, we found significant decrease in histone 3 acetylation in DOX-treated cells. DOX treatment of cultured cardiomyocyte precursor cells causes severe cell death by apoptosis associated with cellular oxidative stress. In addition, significant regulation of proteins involved in epigenetic processes and changes in global histone 3 acetylation were observed. However, the significance and clinical impact of these changes remain elusive.
Assuntos
Doxorrubicina/efeitos adversos , Epigênese Genética/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores/metabolismo , Cardiotoxicidade/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Histona Desacetilases/metabolismo , Histona Desmetilases/metabolismo , Histonas/metabolismo , Peróxido de Hidrogênio/farmacologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , RatosRESUMO
Aims: CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results: Male wild type and CD40L-/- mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L expression, weight, leptin and lipids were increased, and endothelial dysfunction, oxidative stress and inflammation were more pronounced in wild type mice on a high fat diet, all of which was almost normalized by CD40L deficiency. Similar results were obtained in diabetic db/db mice with CD40/TRAF6 inhibitor (6877002) therapy. In a small human study higher serum sCD40L levels and an inflammatory phenotype were detected in the blood and Aorta ascendens of obese patients (body mass index > 35) that underwent by-pass surgery. Conclusion: CD40L controls obesity-associated vascular inflammation, oxidative stress and endothelial dysfunction in mice and potentially humans. Thus, CD40L represents a therapeutic target in lipid metabolic disorders which is a leading cause in cardiovascular disease.