Tamoxifen is an anticancer drug that induces oxidative stress and apoptosis via mitochondria-dependent and nitric oxide (NO)-dependent pathways. The present report shows that tamoxifen increases intramitochondrial ionized Ca 2+ concentration and stimulates mitochondrial NO synthase (mtNOS) activity in the mitochondria from rat liver and human breast cancer MCF-7 cells. By stimulating mtNOS, tamoxifen hampers mitochondrial respiration, releases cytochrome c, elevates mitochondrial lipid peroxidation, increases protein tyrosine nitration of certain mitochondrial proteins, decreases the catalytic activity of succinyl-CoA:3-oxoacid CoA-transferase, and induces aggregation of mitochondria. The present report suggests a critical role for mtNOS in apoptosis induced by tamoxifen. [Cancer Res 2007;67(3):1282-90]

Abstract-The obesity-prone/obesity-resistant rat model has been used to study mechanisms responsible for obesity-related abnormalities in renal function and blood pressure, but whether this model exhibits cardiac dysfunction has not been determined. We tested the hypothesis that obesity-prone rats would display cardiovascular abnormalities seen in other diet-induced obese models (ie, hypertension, tachycardia, left ventricular hypertrophy, increased collagen deposition, reduced cardiac contractility, and increased end diastolic pressure). Male Sprague-Dawley rats were fed a control diet or a moderate fat diet containing 32% kcal as fat while hemodynamics were continuously monitored using telemetry. After 12 weeks, obesity-prone rats were significantly heavier and had greater body fat compared with obesity-resistant rats and controls, but daily (20 hours/d) averages and diurnal rhythms of blood pressure and heart rate did not differ among groups. Echocardiographic indices of cardiac structure and function, histological evidence of cardiac collagen, and directly measured heart weights did not differ among groups. Peak left ventricular pressure, end diastolic pressure, ϩdP/dt, and ϪdP/dt were also not significantly different among groups. Plasma cholesterol and hepatic cholesterol were significantly higher in obesity-prone rats compared with obesity-resistant rats and controls; hepatic triglycerides were higher in obesity-prone rats compared with controls (PՅ0.05). Leptin was significantly higher in obesity-prone rats compared with controls and across all groups was significantly correlated with body fat (PՅ0.05). These results suggest that 12 weeks of a moderate fat diet in the obesity-prone/obesity-resistant rat model induced lipid and endocrine abnormalities typical of obesity but was not sufficient to cause significant cardiac abnormalities. Key Words: hypertrophy Ⅲ echocardiography Ⅲ blood pressure Ⅲ cardiac output Ⅲ rats Ⅲ diurnal rhythm T he prevalence of obesity in the United States has increased in the last several decades, with two-thirds of Americans now considered overweight or obese. 1,2 Obesity decreases life expectancy and increases the incidence of stroke and coronary heart disease. 3 Elucidating mechanisms involved in obesityrelated cardiac dysfunction requires use of appropriate animal models. Genetic models of obesity in rodents such as the ob/ob rat, the Zucker obese rat. and the spontaneously hypertensive obese rat have been used for cardiovascular research. 4,5 However, these models may not exhibit the same abnormalities as do obese humans, such as hypertension, hyperglycemia, hyperinsulinemia, and cardiac hypertrophy. 4,6 In contrast, diet-induced models of obesity in the dog and rabbit have shown promise for studying cardiovascular 7-9 and renal 10 mechanisms involved in obesity-related pathologies.There is little doubt that a rodent model of obesity based on the intake of a high-fat diet would be advantageous in studying obesity-related cardiovascular abnormalities. One such model that has ...

The objective of the present study was to delineate the molecular mechanisms for mitochondrial contribution to oxidative stress induced by hypoxia and reoxygenation in the heart. The present study introduces a novel model allowing real-time studying mitochondria under hypoxia and reoxygenation, and describes the significance of intramitochondrial calcium homeostasis and mitochondrial nitric oxide synthase (mtNOS) for oxidative stress. The present study shows that incubating isolated rat heart mitochondria under hypoxia followed by reoxygenation, but not hypoxia per se, causes cytochrome c release from the mitochondria, oxidative modification of mitochondrial lipids and proteins, and inactivation of mitochondrial enzymes susceptible to inactivation by peroxynitrite. Those alterations were prevented when mtNOS was inhibited or mitochondria were supplemented with antioxidant peroxynitrite scavengers. The present study shows mitochondria independent of other cellular components respond to hypoxia/reoxygenation by elevating intramitochondrial ionized calcium and stimulating mtNOS. The present study proposes a crucial role for heart mitochondrial calcium homeostasis and mtNOS in oxidative stress induced by hypoxia/ reoxygenation.

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