Angiotensin II modulates CD40 expression in vascular smooth muscle cells

The signalling pathway CD40/CD40L (CD40 ligand) plays an important role in atherosclerotic plaque formation and rupture. AngII (angiotensin II), which induces oxidative stress and inflammation, is also implicated in the progression of atherosclerosis. In the present study, we tested the hypothesis that AngII increases CD40/CD40L activity in vascular cells and that ROS (reactive oxygen species) are part of the signalling cascade that controls CD40/CD40L expression. Human CASMCs (coronary artery smooth muscle cells) in culture exposed to IL (interleukin)-1 beta or TNF-alpha (tumour necrosis factor-a) had increased superoxide generation and enhanced CD40 expression, detected by EPR (electron paramagnetic resonance) and immunoblotting respectively. Both phenomena were abolished by previous incubation with membrane-permeant antioxidants or cell transfection with P22(phox) antisense. AngII (50-200 nmol/l) induced an early and sustained increase in CD40 mRNA and protein expression in CASMCs, which was blocked by treatment with antioxidants. Increased CD40 expression led to enhanced activity of the pathway, as AngII-treated cells stimulated with recombinant CD40L released higher amounts of IL-8 and had increased COX-2 (cyclo-oxygenase-2) expression. We conclude that AngII stimulation of vascular cells leads to a ROS-dependent increase in CD40/CD40L signalling pathway activity. This phenomenon may be an important mechanism modulating the arterial injury observed in atherosclerosis-related vasculopathy.

Improved endothelial function with simvastatin but unchanged insulin sensitivity with simvastatin or ezetimibe

In addition to their expected effects on lipid profile, lipid-lowering agents may reduce cardiovascular events because of effects on nonclassic risk factors such as insulin resistance and inflammation. Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol as well as plant sterols. Although it is known that an additional reduction of low-density lipoprotein cholesterol (LDL-C) levels can be induced by the combination of ezetimibe with statins, it is not known if this can enhance some pleiotropic effects, which may be useful in slowing the atherosclerotic process. This study assessed the effects of simvastatin and ezetimibe, in monotherapy or in combination, on markers of endothelial function and insulin sensitivity. Fifty prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia were randomly allocated to 2 groups receiving either ezetimibe (10 mg/d) or simvastatin (20 mg/d) for 12 weeks, after which the drugs were combined for both groups for an additional 12-week period. Clinical and laboratory parameters were measured at baseline and after 12 and 24 weeks of therapy. Homeostasis model assessment of insulin resistance index and the area under the curve of insulin were calculated. As expected, both groups receiving drugs in isolation significantly reduced total cholesterol, LDL-C, apolipoprotein B, and triglyceride levels; and additional reductions were found after the combination period (P <.05). After 12 weeks of monotherapy, plasminogen activator inhibitor-1 levels and urinary albumin excretion were lower in the simvastatin than in the ezetimibe group. No change in homeostasis model assessment of insulin resistance index, area under the curve of insulin, and adiponectin levels was observed tiller either the monotherapies or the combined therapy. However, simvastatin combined with ezetimibe provoked significant reductions in E-selectin and intravascular cellular adhesion molecule-1 levels that were independent of LDL-C changes. Our findings support claims that simvastatin may be beneficial in preserving endothelial function in prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia. Alternatively, a deleterious effect of ezetimibe on the endothelial function is suggested, considering the increase in intravascular cellular adhesion molecule I and E-selectin levels. Simvastatin and ezetimibe, in isolation or in combination, do not interfere with insulin sensitivity. (C) 2010 Elsevier Inc. All rights reserved.

Acute actions of thyroid hormone on blood vessel biochemistry and physiology

Purpose of review Description of the progress about the vascular effects promoted by thyroid hormones. Recent findings Over the past few years, a number of studies have shown that in addition to genomic effects on blood vessels, thyroid hormones exert extranuclear nongenomic effects on vascular smooth muscle cells and endothelium. These nongenomic effects occur rapidly and do not involve thyroid hormone response elements-mediated transcriptional events. In this context, the genomic and nongenomic events promoted by thyroid hormones act in concert to control the vascular hemodynamic and regulate the cardiovascular function. Summary Considering the antiatherogenic property of thyroid hormones and the rapid effects produced by this molecule as a vasodilator, including that in the coronary bed, a better understanding of the molecular mechanisms involved in its action may contribute to the development of drugs that can be clinically used to increase the known benefits promoted by thyroid hormones in cardiovascular physiology.

Granulocyte Colony-stimulating Factor Reduces Mortality by Suppressing Ventricular Arrhythmias in Acute Phase of Myocardial Infarction in Rats

Our aim was to evaluate the effects of granulocyte colony-stimulating factor (G-CSF) on early cardiac arrhythmias after myocardial infarction (MI) and the impact on survival. Male Wistar rats received repeated doses of 50 mu g/kg G-CSF (MI-GCSF group) or vehicle (MI group) at 7, 3, and 1 days before surgery. MI was induced by permanent occlusion of left corollary artery. The electrocardiogram was obtained before occlusion and then for 30 minutes after surgery. Events and duration of ventricular arrhythmias were analyzed. The levels of connexin43 (Cx43) were measured by Western blot immediately before MI production. Survival was significantly increased in MI-GCSF pretreated group (74% versus 52.0% MI. P < 0.05). G-CSF pretreatment also significantly reduced the ventricular premature beats when compared with the untreated-MI group (201 +/- 47 versus 679 +/- 117, P < 0.05). The number and the duration of ventricular tachycardia were smaller in the MI-G-CSF group, as well as the number of ventricular fibrillation episodes (10% versus 69% in NIL P < 0.05). Cx43 levels were significantly increased by G-CSF treatment (1.27 +/- 0.13 versus 0.86 +/- 0.11; P < 0.05). The MI size 24 hours after occlusion was reduced by G-CSF pretreatment (36 +/- 3% versus 44 +/- 2% of left ventricle in MI group; P < 0.05). The increase of Cx43 expression in the heart may explain the reduced incidence in ventricular arrhythmias in the early phases after coronary artery occlusion in rats, thus increasing survival after MI.