digoxin and Atherosclerosis

Numerous in vitro studies have suggested that digoxin suppresses inflammation and alters lipid metabolism. However, the effect of dioxin on atherosclerosis is poorly understood. The present study was conducted to determine whether digoxin affects the development of atherosclerosis in a murine model of atherosclerotic disease.. Apolipoprotein E-deficient mice maintained on a Western-type diet were administered PBS (control), low-dose digoxin (1 mg · kg(-1) · day(-1)) or high-dose digoxin (2 mg · kg(-1) · day(-1)) via i.p. injection for 12 weeks.. Digoxin dose-dependently reduced atherosclerotic lesion formation and plasma lipid levels (reductions of 41% in total cholesterol, 54% in triglycerides and 20% in low-density lipoprotein cholesterol in the high-dose digoxin-treated group). Moreover, treatment with digoxin markedly attenuated IL-17A expression and IL-17A-related inflammatory responses and increased the abundance of regulatory T cells (Tregs).. Our data demonstrate that digoxin acts as a specific antagonist of retinoid-related orphan receptor-γ to decrease atherosclerosis by suppressing lipid levels and IL-17A-related inflammatory responses.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Digoxin; Dose-Response Relationship, Drug; Inflammation; Interleukin-17; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 1, Group F, Member 3

Pro-inflammatory processes initiated in the endothelium represent a crucial step in the pathogenesis of inflammatory cardiovascular disease, such as atherosclerosis. Recent observations pointed to potential anti-inflammatory properties of the cardiac glycoside digitoxin. Therefore, the present study investigated potential anti-inflammatory and vasoprotective properties of digitoxin as well as the underlying signaling pathways affected in endothelial cells (EC). Digitoxin, employing therapeutical concentrations used in patients (3-30nM), potently inhibited the IL-1beta-induced expression of MCP-1 and VCAM-1 in EC and the capacity of corresponding cell culture supernatants on monocyte migration as well as monocyte adhesion to endothelial monolayers, respectively. Furthermore, digitoxin prevented the IL-1beta-induced activation of p44/42-MAPK and NF-kappaB without affecting activation of JNK and p38-MAPK. Inhibition of NF-kappaB signaling but not p44/42-MAPK mimicked the observed inhibitory effects of digitoxin on MCP-1 expression and monocyte migration. Moreover, digitoxin inhibited NF-kappaB signaling at the level of TAK-1/IKK. Additionally, digitoxin prevented TNF-alpha-induced apoptosis in EC accompanied by activation of Akt. Blockade of PI-3-kinase, activator of Akt, prevented the anti-apoptotic properties of digitoxin and impaired its inhibitory action on NF-kappaB signaling and MCP-1 expression. Finally, digitoxin activated endothelial NO-synthase, which was blocked by inhibition of PI-3-kinase, Ca(2+)/Calmodulin-dependent-proteinkinase-II and chelation of intracellular calcium. Digitoxin elicits anti-inflammatory and vasoprotective properties by blocking NF-kappaB and activating PI-3-kinase/Akt signaling as well as Ca(2+)/Calmodulin-dependent-proteinkinase-II in EC. These observations indicate a potential therapeutical application of digitoxin in the treatment of cardiovascular diseases, such as atherosclerosis.

Topics: Anti-Inflammatory Agents; Atherosclerosis; Cell Adhesion; Cells, Cultured; Digitoxin; Digoxin; Endothelial Cells; Enzyme Activation; Humans; I-kappa B Kinase; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Nitric Oxide Synthase Type III; Vascular Cell Adhesion Molecule-1

Clinical autopsy rate have been declining since the 1950s, but it remains a useful investigation tool.. Through six examples of our experience, we underline its interest for clinical, didactic and public health purposes.. We try to understand the reasons for its decline and, as demonstrated, it can be attributed to a number of factors. These need to be addressed in order to reassert the status of the autopsy as an investigation and audit tool which is crucial to the future effectiveness of modern medicine.

Topics: Adult; Aged; Atherosclerosis; Atrial Fibrillation; Autopsy; Cardiotonic Agents; Casuistry; Cause of Death; Coronary Artery Disease; Coronary Thrombosis; Diagnosis, Differential; Digoxin; Education, Medical; Female; France; Hallucinations; Hospitals, University; Humans; Male; Marfan Syndrome; Meningitis, Listeria; Meningitis, Pneumococcal; Middle Aged; Myocardial Infarction