1. The influence of repeated administration of poloxamer 407 on serum lipoproteins and protease activity in mouse liver and heart
- Author
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Korolenko, Tatyana A., Tuzikov, Fedor V., Johnston, Thomas P., Tuzikova, Natalia A., Kisarova, Yana A., Zhanaeva, Svetlana Ya., Alexeenko, Tatyana V., Zhukova, Natalia A., Brak, Ivan V., Spiridonov, Victor K., Filjushina, Elena E., Cherkanova, Marina S., and Monoszon, Anna A.
- Subjects
Physiological aspects ,Dosage and administration ,Macrophages -- Physiological aspects ,Poloxamers -- Physiological aspects -- Dosage and administration ,Lipoproteins -- Physiological aspects ,Proteases -- Physiological aspects ,Heart -- Physiological aspects ,Liver -- Physiological aspects ,Blood lipoproteins -- Physiological aspects ,Proteolipids -- Physiological aspects - Abstract
Introduction Recently, using a novel small-angle X-ray scattering (SAXS) method for the determination of fractional and subfractional composition of lipoproteins (LPs), we showed that a high dose of atorvastatin exerts [...], The effects of repeated administration of poloxamer 407 (P-407) on lipoprotein-cholesterol (LP-C) and lipoprotein-triglyceride (LP-TG) fractions and subtractions, as well as the effect on liver and heart proteases, were studied. Repeated administration of P-407 to male CBA mice resulted in a model of atherosclerosis with increased diastolic blood pressure; there was a drastic increase in total serum cholesterol and especially TG. A novel small-angle X-ray scattering method for the determination of the fractional and subfractional composition of LP-C and LP-TG was used. In chronically P-107-treated mice, P-107 significantly increased atherogenic low-density lipoprotein C (LDL-C) fractions, as well as intermediate-density lipoprotein C (IDL-C), and [LDL.sub.1-3]-C subfractions, and very-low-density lipoprotein-C (VLDL-C) fractions, as well as [VLDL.sub.1-2-C] and [VLDL.sub.3-5]-C subfractions), to a lesser extent, the total anti-atherogenic high-density lipoprotein C (HDL-C) fraction, as well as [HDL.sub.2]-C and [HDL.sub.3]-C subfractions. Additionally, we demonstrated an increase in the serum chitotriosidase activity, without significant changes in serum matrix metalloprotease (MMP) activity. Morphological changes observed in P-407-treated mice included atherosclerosis in the heart and storage syndrome in the liver macrophages. P-407 significantly increased the activity of cysteine, aspartate proteases, and MMPs in the heart, and only the activity of cathepsin B and MMPs in the liver of mice. Thus, repeated administration of P4-07 to mice induced atherosclerosis secondary to sustained dyslipidemia and formation of foamy macrophages in liver, and also modulated the activity of heart and liver proteases. Key words: lipoprotein fractions and subfractions, P-407-induced heart and liver injury, cathepsins B, L, and D, matrix metalloproteases, chitotriosidase. L'effet d'une administration repetee de poloxamer 407 (P-407) sur les fractions et les sous-fractions de lipoproteines-cholesterol (LP-C) et de lipoproteines-triglycerides (LP-TG) ainsi que son effet sur les proteases du foie et du coeur ont ete etudies. L'administration repetee de P-107 chez les souris produisait un modele d'atherosclerose caracterise par une pression sanguine diastolique accrue ; on observait une augmentation radicale du cholesterol total serique et particulierement des TG. Une nouvelle methode de dispersion de rayons-X a angle reduit a ete utilisee pour determiner la composition des fractions et des sous-fractions de LP-C et LP-TG. Lorsqu'administre de facon chronique a des souris, le P-107 augmentait significativement les lipoproteines de faible densite C (LDL-C) atherogenes (sous-fractions lipoproteines de densite intermediaire (IDL-C et [LDL.sub.1-3]-C) et les lipoproteines de tres faible densite-C (VLDL-C) (sous-fractions [VLDL.sub.1-2]-C et [VLDL.sub.3-5]-C) et, dans une moindre mesure, la fraction totale anti-atherogene des lipoproteines de haute densite (HDL-C: sous fractions [HDL.sub.2]-C et [HDL.sub.3]-C). De plus, une augmentation de Factivite chitotriosidase serique etait demontree, alors que l'activite metalloprotease de la matrice (MMP) du serum ne changeait pas significativement. Les changements morphologiques observes chez les souris traitees au P-407 incluaient l'atherosclerose du coeur et le syndrome de stockage des macrophages du foie. Le P4-07 augmentait significativement Factivite des proteases a cysteine, des proteases a aspartate et des MMP dans le coeur, et Factivite de la cathepsine B et des MMP seulement, dans le foie des souris. Ainsi, l'administration repetee de P-407 chez les souris induisait une atherosclerose secondaire a une dyslipemie prolongee et a la formation de macrophages spumeux dans le foie, ainsi qu'une modulation de l'activite des proteases du cour et du foie. Mots-cles : fractions et sous-fractions de lipoproteines, dommage cardiaque et hepatique induit par le P-407, cathepsines B, L et D, metalloproteases de la matrice, chitotriosidase. [Traduit par la Redaction]
- Published
- 2012
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