Decreased nitric oxide (NO) activity, the formation of reactive oxygen species, and increased endothelial expression of the redox-sensitive vascular cell adhesion molecule 1

The use of atorvastatin in patients with nonischemic HF improves LVEF and attenuates adverse LV remodeling. The effects on soluble levels of several inflammatory markers with atorvastatin suggest, in part, mechanisms by which statins might exert their beneficial effects in nonischemic HF.

IntroductionEarly features in the pathogenesis of atherosclerosis include accumulation of oxidized LDL (oxLDL) and endothelial expression of the vascular adhesion molecule VCAM-1.

Background-The metabolic syndrome is associated with increased angiotensin II activity, induction of a proinflammatory and oxidative state, and endothelial dysfunction. We evaluated the ability of irbesartan, an angiotensin receptor blocker, and lipoic acid, an antioxidant, to affect endothelial function and inflammation in patients with the metabolic syndrome. Methods and Results-We randomized 58 subjects with the metabolic syndrome in a double-blinded manner to irbesartan 150 mg/d (nϭ14), lipoic acid 300 mg/d (nϭ15), both irbesartan and lipoic acid (nϭ15), or matching placebo (nϭ14) for 4 weeks. Endothelium-dependent and -independent flow-mediated vasodilation was determined under standard conditions. Plasma levels of interleukin-6, plasminogen activator-1, and 8-isoprostane were measured. After 4 weeks of therapy, endothelium-dependent flow-mediated vasodilation of the brachial artery was increased by 67%, 44%, and 75% in the irbesartan, lipoic acid, and irbesartan plus lipoic acid groups, respectively, compared with the placebo group. Treatment with irbesartan and/or lipoic acid was associated with statistically significant reductions in plasma levels of interleukin-6 and plasminogen activator-1. In addition, treatment with irbesartan or irbesartan plus lipoic acid decreased 8-isoprostane levels. No significant changes in blood pressure were noted in any of the study groups. Conclusions-Administration

The transcriptional nuclear factor (NF)-kappaB can be activated by diverse stimuli such as cytokines, mitogens, oxidative stress, and lipids, leading to the transactivation of several genes that play important roles in the development of atherosclerosis. Because oxidative stress may play a key role in the pathogenesis of diabetic vascular disease, we have examined whether culture of porcine vascular smooth muscle cells (PVSMCs) under high glucose (HG) conditions (25 mmol/l) to simulate the diabetic state can lead to the activation of NF-kappaB, and also whether cytokine- or growth factor-induced NF-kappaB activation is altered by HG culture. We observed that PVSMCs cultured in HG showed significantly greater activation of NF-kappaB in the basal state compared with cells cultured in normal glucose (NG) (5.5 mmol/l). Treatment of the cells with cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1beta, or with growth factors, such as platelet-derived growth factor, insulin-like growth factor-I, and epidermal growth factor, all led to NF-kappaB activation in cells cultured in both NG and HG. However, their effects were markedly greater in HG. The augmented TNF-alpha-induced NF-kappaB activation in HG was associated with increased TNF-alpha-mediated transcriptional activation of the vascular cell adhesion molecule-1 promoter. Immunoblotting with an antibody to the p65 subunit of NF-kappaB indicated that the levels of this protein were higher in the nuclear extracts from cells cultured in HG compared with NG. Cells cultured in HG also produced significantly greater amounts of the reactive oxygen species superoxide. HG-induced NF-kappaB activation was inhibited by a protein kinase C inhibitor, calphostin C. These results suggest that hyperglycemia-induced activation of NF-kappaB in VSMCs may be a key mechanism for the accelerated vascular disease observed in diabetes.

No abstract

Yoga therapy offered additional benefits to the standard medical care of predominantly AA HF patients by improving cardiovascular endurance, QoL, inflammatory markers, and flexibility.

Background-Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood. Methods and Results-We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4Ϯ8.5 minutes; nϭ10) compared with control mice (54.5Ϯ35.5 minutes, nϭ10, Pϭ0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of DL-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability. Conclusions-Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.