title: Early-stage atherosclerosis in poloxamer 407-induced hyperlipidemic mice: pathological features and changes in the lipid composition of serum lipoprotein fractions and subfractions.
abstract: BACKGROUND
  The aims of this study were to evaluate the effect of poloxamer 407 administration on atherogenic serum lipoprotein fractions and subfractions associated with cholesterol, triglycerides and phospholipids, as well as the onset of early atherosclerosis, in mice.
  
  
  METHODS
  Mice were administered either sterile saline or poloxamer 407 (to induce a dose-controlled hyperlipidemia) for 1 month and then sacrificed at 1, 4 and 10 days after the last dose of poloxamer 407. Systolic and diastolic blood pressure, the activity of a cysteine protease (cathepsin B) in cardiac and liver tissue, and histological/morphological examination of heart and liver specimens was performed for each group of mice at each time point. Lastly, small angle X-ray scattering was utilized to analyze the lipoprotein fractions and subfractions associated with cholesterol, triglycerides and phospholipids for both groups of mice at each time point. Statistical analysis was performed using one-way, analysis-of-variance with post hoc analysis to determine significantly different mean values, while correlation analysis employed the Spearman test.
  
  
  RESULTS
  Poloxamer 407-treated mice revealed significant hyperlipidemia, moderately elevated blood pressure, general lipidosis in liver cells, increased cysteine protease activity in heart tissue, and contractile-type changes in cardiomyocytes. Similar to humans, the onset of atherosclerosis in poloxamer 407-treated mice was characterized by a steady increase in serum low-density, intermediate-density and very-low-density lipoprotein fractions, as well as very-low-density lipoprotein subfractions.
  
  
  CONCLUSIONS
  We would propose that the sustained elevation of serum atherogenic lipoprotein fractions and subfractions induced by the administration of poloxamer 407 to mice resulted in the morphological changes we observed in both heart and liver cells, which are suggested to precede atherosclerosis, since this is a well-established mouse model of atherosclerosis. Since most of the cellular, biochemical and physiological changes documented in the present study using poloxamer 407-treated mice are related to the symptoms of early atherosclerosis in humans, it is suggested that the poloxamer 407-induced mouse model of hyperlipidemia and atherosclerosis might prove beneficial as an experimental animal model with which to evaluate the pathological features observed in early-stage atherosclerosis.
authors.affiliation: Institute of Physiology and Fundamental Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Timakov St. 4, Novosibirsk, 630117, Russia. t.a.korolenko@physiol.ru.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Korolenko
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Rm. 4243, HSB, 2464 Charlotte Street, Kansas City, MO, 64108-2718, USA. johnstont@umkc.edu.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Johnston
authors.affiliation: Boreskov Institute of Catalysis, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. tuzikov@catalysis.ru.|Novosibirsk State University, Novosibirsk, Russia. tuzikov@catalysis.ru.
authors.forename: Fedor V
authors.initials: FV
authors.lastname: Tuzikov
authors.affiliation: Boreskov Institute of Catalysis, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. tuzikova@catalysis.ru.|Novosibirsk State University, Novosibirsk, Russia. tuzikova@catalysis.ru.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Tuzikova
authors.affiliation: Novosibirsk State Medical University, Novosibirsk, Russia. apupyshev@mail.ru.
authors.forename: Alexandr B
authors.initials: AB
authors.lastname: Pupyshev
authors.affiliation: Institute of Physiology and Fundamental Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Timakov St. 4, Novosibirsk, 630117, Russia.
authors.forename: Victor K
authors.initials: VK
authors.lastname: Spiridonov
authors.affiliation: Institute of Physiology and Fundamental Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Timakov St. 4, Novosibirsk, 630117, Russia. natalya15.ru@rambler.ru.
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Goncharova
authors.affiliation: Siberian Division of the Russian Academy of Sciences, Institute of Chemical Biology and Basic Medicine, Novosibirsk, Russia. imai@mail.ru.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Maiborodin
authors.affiliation: Vorozhtzov N.N. Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. GNA2004@ngs.ru.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Zhukova
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D050197:Atherosclerosis / Q000097:blood* / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D002401:Cathepsin B / Q000378:metabolism; D003971:Diastole; D006949:Hyperlipidemias / Q000097:blood* / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D007425:Intracellular Membranes / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008808:Mice, Inbred CBA; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010539:Permeability; D020442:Poloxamer / Q000008:administration & dosage; D013599:Systole; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D008074:Lipoproteins; D020442:Poloxamer; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002401:Cathepsin B