Recent evidence suggests that mutant huntingtin protein-induced energetic perturbations contribute to neuronal dysfunction in Huntington's disease (HD). Given the ubiquitous expression of huntingtin, other cell types with high energetic burden may be at risk for HD-related dysfunction. Early-onset cardiovascular disease is the second leading cause of death in HD patients; a direct role for mutant huntingtin in this phenomenon remains unevaluated. Here we tested the hypothesis that expression of mutant huntingtin is sufficient to induce cardiac dysfunction, using a well-described transgenic model of HD (line R6/2). R6/2 mice developed cardiac dysfunction by 8 weeks of age, progressing to severe failure at 12 weeks, assessed by echocardiography. Limited evidence of cardiac remodeling (e.g. hypertrophy, fibrosis, apoptosis, β 1 adrenergic receptor downregulation) was observed. Immunogold electron microscopy demonstrated significant elevations in nuclear and mitochondrial polyglutamine presence in the R6/2 myocyte. Significant alterations in mitochondrial ultrastructure were seen, consistent with metabolic stress. Increased cardiac lysine acetylation and protein nitration were observed, and were each significantly associated with impairments in cardiac performance. These data demonstrate that mutant huntingtin expression has potent cardiotoxic effects; cardiac failure may be a significant complication of this important experimental model of HD. Investigation of the potential cardiotropic effects of mutant huntingtin in humans may be warranted.

Peroxynitrite formation has been demonstrated in several neurodegenerative disorders; thus far, protein nitration and consequent alterations in protein function are implicated as mechanistic events. Free 3-nitrotyrosine (free-3NT) is also elevated in these settings; a neurotoxic role for this modified amino acid has not been investigated. We tested the hypothesis that free-3NT is neurotoxic in vivo, using a mouse model of striatal degeneration. The neurodegenerative effects of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) (unilateral intrastriatal injection, 64 nmol) were compared with free-3NT (32 nmol) or free-tyrosine (free-TYR) (32 nmol). 6-OHDA-treated mice exhibited significant ipsilateral turning behavior after d-amphetamine challenge, indicative of unilateral striatal injury (ipsilateral-contralateral turning differential, 21.1 +/- 6.8). Significant turning behavior was also observed in free-3NT-treated mice but not in free-tyrosine-treated mice (free-3NT, 16.0 +/- 3.9; free-TYR, 1 +/- 2.7; p < 0.01). Immunohistochemistry was used to evaluate striatal tyrosine hydroxylase (TH) content. 6-OHDA or free-3NT treatment caused severe reductions in TH immunoreactivity in injected striata compared with the contralateral hemisphere (injected/contralateral immunoreactivity ratio: 6-OHDA, 0.23 +/- 0.07; free-3NT, 0.49 +/- 0.02). Free-tyrosine treatment had no effect (1.03 +/- 0.09). Turning behavior was correlated with striatal TH ratio (p < 0.01). Furthermore, we observed a striking unilateral reduction in TH-positive cell body counts in the substantia nigra pars compacta of 6-OHDA- and free-3NT-treated mice (injected/contralateral cell count ratio: 6-OHDA, 0.40 +/- 0.04; free-3NT, 0.59 +/- 0.02). Free-tyrosine treatment had no effect (1.05 +/- 0.04). No evidence for increased striatal protein incorporation of 3NT was observed in any treatment group. These data represent the first evidence that free-3NT can elicit neurodegenerative effects in vivo; free-3NT may have a causal role in neurodegenerative conditions.

ABSTRACT:In the present study, we tested the hypothesis that exposure of newborn mice to sublethal hyperoxia would alter lung development and expressions of fibroblast growth factor receptors (FGFRs)-3 and FGFR-4. Newborn FVB mice were exposed to 85% O 2 or maintained in room air for up to 14 d. No animal mortality was observed, and body weight gains were not affected by hyperoxia. At postnatal d 7 and 14 (P7, P14), lungs of mice exposed to 85% O 2 showed fewer alveolar secondary crests and larger alveoli or terminal air spaces than did mice in room air. In pups kept in room air, lung levels of FGFR-3 and FGFR-4 mRNA were greater at P3 than at P1, but similar increases were not observed in hyperoxic mice. Immunoreactivity of FGFR-3 and FGFR-4 was lower in lungs of hyperoxic mice than in controls at P14. In pups kept in room air, lung fibroblast growth factor (FGF)-7 mRNA levels were greater at P14 than at P1, but similar changes were not observed in hyperoxic mice. The temporally and spatially specific alterations in the expressions of FGFR-3, FGFR-4, and FGF-7 in the mice exposed to hyperoxia may contribute to aberrant lung development. B ronchopulmonary dysplasia (BPD) was described initially as lung injury-and repair-related effects that were associated with radiologic findings of streaky, fibrous densities, alternating with hyperlucent areas (1,2). The primary risk factors were premature birth, respiratory distress, mechanical ventilation, and administration of supplemental oxygen (FIO 2 Ͼ0.21). Inflammation, problems in nutritional support, and comorbid conditions also contribute to the development of BPD. Modifications of therapeutic strategies have decreased the incidence of BPD, as the disease was described originally, but the overall incidence of BPD has not declined. The "new BPD" of recent years shows little acute injury and repair described by Northway et al. (1,2), but is characterized by fewer and larger alveoli and less organized alveolar vascularization, suggesting arrested or disordered lung development. The events occurring during secondary septation of terminal gas exchange units and maturation of alveolar microvasculature are therefore of particular interest in research on mechanisms responsible for the new BPD (3-8).Lung development in humans normally progresses through sequential structural changes that are observed similarly in rats and mice, which, at term, exhibit lungs that structurally resemble human lungs at 26 -30 wk of gestation (9). Infants born at this age frequently encounter respiratory problems, arising from immature pulmonary surfactant metabolism, respiratory drive and coordination, or other deficiencies. Prematurely delivered nonhuman primate models of BPD may mimic human development more closely than do rodent models, but practical constraints limit the investigations that can be explored with primate models (4,5,10).The lungs of newborn rodents are sufficient for extrauterine life and are adequate for maturation into normal adult lungs. Studies in rats and mice indicate th...

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