Abstract-The mechanism(s) by which exercise reduces atherogenic risk remains unknown. This study tested the hypothesis that sustained exercise-induced oxidative stress may increase antioxidant defense in the arterial wall. Acute exercise induced an increase in antibodies to oxidatively modified proteins and catalase in the aortic walls of normal mice compared with sedentary control mice. In male atherogenic diet-fed low density lipoprotein (LDL) receptordeficient mice, exercise lowered plasma cholesterol (15%) and decreased atherosclerotic lesions by 40% compared with values in sedentary control mice, with a concomitant increase in arterial catalase and endothelial NO synthase. Because these mice lack the LDL receptor, the results indicate that the LDL receptor might not be responsible for the exercise-induced lowering of plasma cholesterol. Vitamin E supplementation to exercising LDL receptor-deficient mice did not reduce atherosclerotic lesion formation significantly as opposed to lesion formation in untreated exercised mice. Moreover, vitamin E counteracted the beneficial effects of exercise by preventing the induction of aortic catalase activity and endothelial NO synthase expression. These results might indicate that although vitamin E might have prevented the exercise-induced oxidative stress, its availability in the artery was insufficient to prevent the atherosclerotic process.These results indicate that exercise-induced plasma oxidative stress could be responsible for the prevention of atherosclerosis by stimulating arterial antioxidant response. Furthermore, vitamin E supplementation could be deleterious in exercisers by inhibiting antioxidant enzyme buildup in the arterial wall. (Arterioscler Thromb Vasc Biol.

Nitric oxide (NO) was found to inhibit the copper-dependent induction of the yeast CUP1 gene. This effect is attributable to an inhibition of the copper-responsive CUP1 transcriptional activator Ace1. A mechanism is proposed whereby the metal binding thiols of Ace1 are chemically modified via NO-and O 2-dependent chemistry, thereby diminishing the ability of Ace1 to bind and respond to copper. Moreover, it is proposed that demetallated Ace1 is proteolytically degraded in the cell, resulting in a prolonged inhibition of copper-dependent CUP1 induction. These findings indicate that NO may serve as a disrupter of yeast copper metabolism. More importantly, considering the similarity of Ace1 to other mammalian metal-binding proteins, this work lends support to the hypothesis that NO may regulate͞disrupt metal homeostasis under both normal physiological and pathophysiological circumstances. For example, NO generated by vascular endothelial cells is a messenger molecule involved in the maintenance of vascular tone via interaction with the heme enzyme guanylate cyclase (2). Nitric oxide is also involved in central nervous system function, where it serves as an activator of guanylate cyclase (3). Thus, in its role as a mediator of vascular tone and as a signal transduction agent in the central nervous system, NO appears to act primarily by activating guanylate cyclase, leading to increased levels of the cellular messenger cGMP. However, NO generated from activated macrophages during an immune response is thought to have cytotoxic and͞or cytostatic properties against target organisms in a largely cGMP-independent fashion (4). One important cGMP-independent function of NO is as a regulator of cellular iron metabolism (5), as NO has been found to alter the activity of iron regulatory protein, an important protein involved in the maintenance in iron homeostasis (6). It is likely that alterations in metal metabolism elicited by NO may represent an important aspect of its pathophysiology.It appears that one important aspect of NO physiology and pathophysiology involves its interactions with protein thiols. That is, the activation and inactivation of thiol-containing proteins by NO are thought to be responsible for some of the biological actions of NO (for reviews, see refs. 7-9). Recent and profound discoveries in the yeast Saccharomyces cerevisiae indicate that the intracellular transport, sequestration, and uptake of metals occurs through the actions of many thiol-containing proteins. For example, the yeast copper chaperones Lys7, Atx1, Cox17, and Ccc2 all appear to bind copper via thiol ligation (ref. 10 and references therein). Also, the yeast metallothioneins sequester ''free'' copper by using thiol-rich metal binding domains (11). Finally, the yeast metal-responsive transcription factors Ace1 and Mac1 are responsible for the expression of a variety of metal regulatory proteins and appear to respond to copper by binding it in an analogous fashion to metallothionein (12-16). Considering the known chemical and biochemical i...

No abstract

No abstract