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Objective-We investigated the effects of fluvastatin on hypoxia-induced (1 to 3 weeks, 10% O 2 ) pulmonary hypertension with focus on endothelial nitric oxide synthase (eNOS) activity. Methods and Results-Oral fluvastatin treatment (1 mg/kg daily) prevented the causing and progression of pulmonary hypertension as determined by the right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary artery. We also revealed that fluvastatin treatments prevented the hypoxia-induced decrease in cGMP production in the rat lung and restored the endothelium-dependent relaxation in the pulmonary artery. We revealed that this beneficial effect was not dependent on the increase in eNOS mRNA or protein expression, but was dependent on the inhibition of the eNOS-tight coupling with caveolin-1, the eNOS dissociation from heat shock protein 90, and the decrease in eNOS Ser 1177 -phosphorylation induced by hypoxia. Furthermore, in a whole-mount immunostaining the hypoxia-induced eNOS protein condensation with caveolin-1 of pulmonary endothelial cells was restored by the fluvastatin-treatment. Key Words: endothelial nitric oxide synthase Ⅲ fluvastatin Ⅲ hypoxia H ypoxia commonly occurs in patients with cardiopulmonary disease and in normal individuals at high altitudes. Chronic hypoxia causes sustained pulmonary hypertension, which is characterized by elevated pulmonary arterial pressure, in association with right ventricular hypertrophy, polycythemia, and pulmonary vascular muscularization. Various forms of pulmonary hypertension pose a significant medical problem and the current options for effective prevention and therapy are limited. 1,2 There is evidence that endothelial dysfunction is intimately involved in the onset and progression of pulmonary hypertension through abnormalities in the production, release, or degradation of endothelium-derived factors, primarily nitric oxide (NO) and endothelin-1. 3,4 In fact, endothelial NO synthase (eNOS) is a candidate gene for vascular genetherapy in pulmonary hypertension. 5 eNOS activity is regulated by a variety of factors such as eNOS-caveolin-1 and eNOS-heat shock protein 90 (HSP90) interactions, 6,7 and eNOS Ser 1177 -phosphorylation by serine/threonine kinase Akt. 6,8 In a previous study, we clarified the mechanisms responsible for the impairment of endothelium-dependent NO production at the eNOS post-transcriptional level in pulmonary hypertension using pulmonary arteries isolated from hypoxia-induced pulmonary hypertensive rats. 9 Notably, the level of eNOS Ser 1177 -phosphorylation, which is an index of eNOS activation, was decreased in hypoxic pulmonary arteries, and that may be mediated by the tight coupling between eNOS and caveolin-1. Conclusion-TheseStatins, 3-hydroxyl-3-methylglutaryl coenzyme A (CoA) (3-hydroxy-3-methylglutaryl [HMG]-CoA) reductase inhibitors, have been developed as lipid-lowering drugs. 10 However, recent experiments and clinical trials have demonstrated that statins also exert vasculoprotective effects independent of their c...

We explored the role of the transcription factor c-Fos in lipopolysaccharide (LPS)-induced cytokine response using mice lacking c-Fos (Fos-/- mice). Compared with wild-type controls, Fos-/- macrophages and mice showed significantly enhanced production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12 p40, but reduced production of the anti-inflammatory cytokine IL-10. Bandshift analysis revealed that LPS-induced NF-kappaB binding activity to a functional site in the TNF-alpha promoter was significantly higher in Fos-/- than in wild-type macrophages. Using telemetry, we monitored body temperature and heart rate after LPS injection and found that Fos-/- mice undergo more severe hypothermia and bradycardia than wild-type mice. Such shock responses in Fos-/- mice were significantly reversed by neutralizing TNF-alpha. These data reveal a novel in vivo role for c-Fos as an anti-inflammatory transcription factor acting through suppression of NF-kappaB activity.

We have studied the autonomic nervous function in voles (Microtus arvalis) and mice. For this purpose, ECGs were recorded from conscious and unrestrained voles and mice using radiotelemetry and the autonomic nervous function was investigated by the power spectral analysis of heart rate variability. Heart rate in voles was lower than mice and the coefficient of variance was larger in voles. In the power spectra of voles and mice, there were two major spectral components with the high frequency (HF) peak generally appearing between 2.0 and 4.0 Hz, and the low frequency (LF) peak appearing below 0.6 Hz. On the basis of this data, we set the two frequency bands as LF (0.1-1.0 Hz) and HF (1.0-5.0 Hz) to evaluate autonomic nervous function. The LF and HF powers were larger in voles than mice. The LF/HF ratio was thought to provide a convenient index of autonomic nervous balance and was smaller in voles than mice. The LF powers in both species were reduced by atropine, but propranolol reduced the LF power only in mice. The HF power was reduced by atropine only in voles. The intrinsic heart rate produced by a double blockade with atropine and propranolol in voles was almost the same as control levels, but in mice was lower than controls. The ratio of the LF and HF powers by a double blockade were almost the same as those of the administration of atropine in voles, but nearer to propranolol in mice. These results suggested that the parasympathetic nervous function was predominant in voles, but the sympathetic one was predominant in mice.

SummaryWe studied the influence of training on autonomic nervous function in the horse. For this purpose, Holter electrocardiogram (ECG) was recorded before and after training from 24 Thoroughbred horses (2-year-olds) and autonomic nervous function was evaluated by the power spectral analysis of heart rate (HR) variability. We obtained HR, low-frequency (LF) power, high-frequency (HF) power, and LFRIF ratio from recording. We set LF at 0.014.07 Hz and HF at 0.0746 Hz. The HF power is thought to reflect primarily parasympathetic nervous function. Both the sympathetic and parasympathetic nervous systems have been shown to contribute to the LF power. The LF/HF ratio is considered as an index of the cardiac sympathovagal balance. Second degree atrioventricular blocks were found in the ECG of 3 and 5 horses before and after the training period, respectively. Ventricular premature depolarisations were detected in a horse after the training period. Heart rate decreased at night. The lowest HR values had a tendency to appear in the early morning. Both the LF and HF power tended to be higher at night. However, the LFRIF ratio was almost the same throughout the day. The HR was significantly decreased by training. Although the LF power and LF/HF ratio were significantly increased, the HF power was not changed by training. These results suggest that parasympathetic nervous activity may be fully activated even before training in this species.

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These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.