Biomedical subjects

J F Keaney

Publications and source records attributed to J F Keaney.

75 records · Page 5Linked to original sources

PubMedDate not supplied

Atherosclerosis, oxidative stress, and antioxidant protection in endothelium-derived relaxing factor action.

The vascular endothelium plays a central role in the regulation of vascular function. In particular, the local release of endothelium-derived relaxing factor (EDRF) regulates vascular tone and prevents platelet adhesion to the vascular wall. Impairment of EDRF action develops early in atherosclerosis and, in part, contributes to platelet deposition and vasospasm involved in the clinical expression of coronary artery disease. Recent evidence suggests that an imbalance between vascular oxidative stress and antioxidant protection is involved in the development of this vascular dysfunction. In this report, the relation between oxidative stress, atherosclerosis, and abnormal EDRF action is reviewed with particular attention to the effects of antioxidant supplementation in animal models of atherosclerosis and hypercholesterolemia.

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PubMedDate not supplied

Atherosclerosis: from lesion formation to plaque activation and endothelial dysfunction.

Atherosclerosis is an important source of morbidity and mortality in the developed world. Despite the fact that the association between LDL cholesterol and atherosclerosis has been evident for at least three decades, our understanding of exactly how LDL precipitates atherosclerosis is still in its infancy. At least three working hypotheses of atherosclerosis are now nearing the stage where their critical evaluation is possible through a combination of basic science investigation and murine models of atherosclerosis. As we move forward in our understanding of this disease, efforts will be increasingly focused on the molecular mechanisms of disease activation that precipitate the clinical manifestations of atherosclerosis such as heart attack and stroke. Two candidates for such investigation involve the events surrounding plaque activation and endothelial dysfunction. Further investigation in these fields should provide the necessary insight to develop the next generation of interventions that will reduce the clinical manifestations of this devastating disease. The purpose of this work is to review the major theories of atherogenesis, examine the aspects of atherosclerosis that lead to disease activation and discuss aspects of disease activation that are amenable to treatment.

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PubMedDate not supplied

Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2.

Increased plasma levels of homocysteine are an independent risk factor for atherothrombosis. While the endothelial cytotoxicity of homocysteine has been attributed to oxidative stress associated with the reactivity of the thiol group, the oxidative effect of homocysteine on vascular smooth-muscle cells has not been investigated. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS), or Nos2 gene product, in vascular smooth-muscle cells may, in part, promote atherosclerosis by increasing local oxidative stress. We therefore hypothesized that homocysteine contributes to atherosclerosis by affecting cytokine-induced production of nitric oxide (NO) by vascular smooth-muscle cells. Confluent rat aortic smooth-muscle cells were exposed to a range of concentrations of homocysteine for 4 hr, then were treated with interferon-gamma, interleukin-1 beta, and lipopolysaccharide to induce iNOS. Media NOx content (nitrite plus S-nitrosothiol) was measured over 24 hr using the Saville reaction. As compared to controls, 5, 50, and 500 microM homocysteine produced a dose-dependent increase in media NOx content, an effect that was primarily a consequence of increased S-nitrosothiol production. iNOS enzyme activity and iNOS protein levels were increased significantly in the homocysteine-treated cells as compared with controls. Northern analysis showed that homocysteine treatment increased steady-state Nos2 mRNA levels by 61% at 6 hr as compared with controls, an effect that was not caused by changes in message stability. By electrophoretic mobility shift assay, homocysteine activated NF-kappa B and also potentiated cytokine activation of NF-kappa B. These data demonstrate that exposure of vascular smooth-muscle cells to pathophysiologically relevant concentrations of homocysteine prior to cytokine stimulation leads both to an increase in NO production and to an NF-kappa B-mediated increase in Nos2 transcription. Upregulation of Nos2 may contribute to the inflammatory response that characterizes early atherogenesis and may, in part, account for the adverse vascular effects of hyperhomocysteinemia.

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