Novel insights into the development of atherosclerosis in hemophilia A mouse models.

BACKGROUND: Cardiovascular diseases in aging people with hemophilia (PWH) represent a growing concern. The underlying hypocoagulability probably provides a protective effect against acute thrombus formation, but the limited data available show no preventive effect against the development of atherogenesis in PWH. Atherosclerosis-prone mice are attractive tools for the study of atherosclerosis development, and may provide insights into disease progression in PWH. METHODS: Severe hemophilia A (factor VIII-deficient [FVIII(o)]) mice were crossed with mice lacking apolipoprotein E (ApoE(-/-)) or mice lacking the LDL receptor (LDLR(-/-)), and then compared to hemostatically normal littermate controls. After mice had received atherogenic diets for 8, 22 or 37 weeks, atherosclerotic lesion size and phenotypic characterization were analyzed in the aortic sinus and whole aortas. RESULTS: ApoE(-/-)/FVIII(o) mice showed a time-dependent protective effect against the development of atherosclerosis, beginning after 22 diet-weeks and persisting to 37 diet-weeks in both the aorta sinus and whole aorta as compared with ApoE(-/-) mice. Notably, the FVIII deficiency did not influence the progression of atherosclerosis in the FVIII(o)/LDLR(-/-) model as compared with controls at early or late time points. CONCLUSIONS: Hypocoagulability ameliorates vascular disease in the ApoE-deficient model in a lipid-independent manner. Interestingly, FVIII deficiency did not affect the development of atherosclerosis in LDLR(-/-) mice. In contrast to the ApoE model, the LDLR model resembles the lipid profile that is commonly observed in humans with atherosclerosis. These findings, to a certain extent, support the notion of atherosclerosis development in the complete absence of FVIII.

Evaluation of the host response to endotoxemia of FVIII and FIX deficient mice.

For several years, coagulation has been implicated in the pathogenesis of sepsis. However, results from clinical trials with natural anticoagulants, as well as studies with knock-out mice for specific coagulation factors yielded conflicting results on the role of coagulation in the pathogenesis of sepsis. The aim of this study was to evaluate the impact of severe The factor VIII:C (FVIII:C) and factor IX:C (FIX:C) deficiency on a lipopolysaccharide (LPS)-induced murine model of sepsis. FVIII:C and FIX:C deficient mice, and their haemostatic normal littermate controls were challenged with LPS, and several parameters of the host response were evaluated: seven-day survival experiments were performed using two dose levels of LPS; biochemical and histological markers of tissue damage, coagulation parameters, and pro-inflammatory cytokines were evaluated at baseline and after 3 h and 6 h after an injection of LPS. Severe FVIII and FIX deficiency were compatible with normal survival in experimental sepsis. In addition, LPS-induced tissue damage and coagulation activation were similar in FVIII or FIX deficient mice compared to their respective controls. A lower release of pro-inflammatory cytokines was observed in FIX but not in FVIII deficient mice. Severe FIX or FVIII deficiency does not protect mice from mortality or from tissue damage in the endotoxemia model, supporting the hypothesis that FVIII and FIX are not critical to the pathogenesis of experimental sepsis.

Utilização de duas diferentes megadoses de vitamina c na ração de alevinos de tilápia do nilo (oreochromis niloticus) submetidos à infecção experimental por edwardsiella tarda

ABSTRACT Aiming to evaluate the effect of supplementation with megadoses of vitamin C on the diet of fingerlings from Nile Tilapia (Oreochromis niloticus), at the experimental infection by Edwardsiella tarda, two experiments were performed. Each experiment was composed by four distinct groups: those belonging to groups 1 and 4 received only commercial diet featuring about 300 mg of vitamin C per kilogram of feed, while the animals belonging to groups 2 and 3 received the same diet supplemented with 1,500 mg and 3,000 mg, respectively, of vitamin C (Lutavit® C Monophosphate BASF) per kilogram of feed. In the first experiment the animals received the diet for 14 consecutive days, being infected on the 15th day, while in the second experiment the animals were infected by the bacterial suspension after an interval of more 14 days after the same period of supplementation with vitamin C. The results showed that although there isnt a significant difference (p > 0,05) with respect to the concentrations of vitamin C, however the interval between the end of supplementation with megadoses of vitamin C in the diet (Nutripeixe AL55 PURINA) and bacterial exposure showed significant difference (p 0,05) on the experimental infection with E. tarda in fingerlings of Nile Tilapia (O. niloticus).

RESUMO Objetivando avaliar o efeito da suplementação com megadoses de vitamina C na dieta de alevinos de Tilápia do Nilo ( Oreochromis niloticus), frente à infecção experimental por Edwardsiella tarda, foram realizados dois experimentos. Cada experimento foi composto por quatro grupos distintos: aqueles pertencentes aos grupos 1 e 4 receberam apenas ração comercial apresentando cerca de 300 mg de vitamina C por quilo de ração, enquanto os animais pertencentes aos grupos 2 e 3 receberam a mesma ração suplementada com 1.500 mg e 3.000 mg, respectivamente, de vitamina C (Lutavit® C Monophosphate BASF) por quilo de ração. No primeiro experimento os animais receberam a dieta durante 14 dias consecutivos, sendo desafiados no 15º dia, enquanto no segundo experimento os animais só foram desafiados pela suspensão bacteriana após um intervalo de mais 14 dias findo o mesmo período de suplementação com vitamina C. Os resultados mostraram que, embora não haja diferença significativa (p > 0,05) com relação às concentrações de vitamina C, o intervalo entre o final do período de suplementação com megadoses de vitamina C na ração (Nutripeixe AL55 PURINA) e a exposição à suspensão bacteriana apresentou diferença significativa (p 0,05) sobre a infecção experimental com E. tarda em alevinos de Tilápia do Nilo (O. niloticus).