Effect of poloxamer 407 administration on the serum lipids profile, anxiety level and protease activity in the heart and liver of mice
Prof. Tatyana Korolenko MD., PhD.
, Thomas P. Johnston
, Nina I. Dubrovina
, Yana A. Kisarova
, Svetlana Ya. Zhanaeva
, Marina S. Cherkanova
, Elena E. Filjushina
, Tatyana V. Alexeenko
, Eva Machova
, and Natalya A. Zhukova
1 Institute of Physiology Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Timakov St. 4, 630117, Russia TEL.: +7 383 3348956, FAX +7 383 3359754
2 University of Missouri-Kansas City, Kansas City, MO 64108, USA
3 Institute of Physiology, Siberian Branch of Russian Academy of Medical Sciences, Novosibirsk, Russia
4 Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
5 Voroztzov’s Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia
Chronic administration of the poloxamer 407 (P-407), a block copolymer, to elevate serum lipids in mice is a well-established mouse model of hyperlipidemia and atherosclerosis. We tested the hypothesis that the activity of several types of proteases in heart and liver tissue is changed in the early stages of atherosclerosis development. Additionally, we evaluated whether increased serum lipids would induce anxiety in mice, as determined by using a ‘plus-maze’ test. The mice were administered P-407 by intraperitoneal injection twice a week for one month. P-407 administration to mice resulted in a marked increase in total serum cholesterol, atherogenic non-HDLcholesterol, and especially in total triglycerides, and it also increased anxiety. Morphological changes observed in P-407-treated mice included contractile type changes in cardiomyocytes and foamy macrophages in liver. A significant increase of cysteine proteases cathepsin B and cathepsin L (at 24 h) and aspartate protease cathepsin D (at both 24 h and 5 days) was determined in heart tissue following P-407 administration. However, no changes were noted in heart matrix metalloproteinase activity. The activity of cysteine and aspartate proteases was significantly increased in liver at both 24 hours and 5 days after P-407 administration. In conclusion, administration of P-407 to mice for one month resulted in increased anxiety, and more importantly, there was an increase in the activity of heart and liver proteases secondary to sustained dyslipidemia. It is suggested that heart and liver cysteine and aspartate proteases may represent potential therapeutic targets in the early stages of atherosclerosis.
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Albert CM, Chae CU, Rexrode KM, Manson JE and Kawachi I. (2005). Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 111: 480-487.
Baskin-Bey ES, Canbay A, Bronk SF, Werneburg N, Guicciardi ME, Nyberg SL and Gores GJ. (2005). Cathepsin B inactivation attenuates hepatocyte apoptosis and liver damage in steatotic livers after cold ischemia-warm reperfusion injury. Am J Physiol Gastrointest Liver Physiol 288: G396-402.
Barrett A and Kirschke H. (1981). Cathepsin B, cathepsin H and cathepsin L. Meth Enzymol 80. Pt C: 535-561.
Bellosta S and Bernini F. (2005) Modulation of macrophage function and metabolism. Hndb. Exp. Pharmacol. (HEP) 170: 665-695.
Brix K, Dunkhorst A, Mayer K and Jordans S. Cysteine cathepsins: cellular roadmap to different functions. (2008) Biochimie 90: 194-207.
Bromme D and Wilson S. (2011). Role of cysteine cathepsins in extracellular proteolysis. Extracellular Matrix Degradation. Biology of Extracellular Matrix, Vol. 2, 23-51.
Chow AK, Cena J and Schulz R. (2007). Acute actions and novel targets of matrix metallopro-teases in the heart and vasculature. Br J Pharmacol 152: 189-205.
Cudic M and Fields GB. (2009). Extracellular proteases as targets for drug development. Curr Protein Pept Sci 10: 297-307.
Cullen P, Rauterberg J and Lorkowski S. (2005). The pathogenesis of atherosclerosis. In: Handb. Exp. Pharmacol. (HEP) (Springer-Verlag,Berlin, Heidelberg), 170 Atherosclerosis, Diet and Drugs. Pt.1: 3-70.
Derosa G, Maffioli P, D’Angelo A, Salvadeo SA, Ferrari I, Fogari E. et al. (2009). Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in combined dyslipidemia. Clin Invest Med 32: E124- E132.
Inami Y, Yamashina S, Izumi K, Ueno T, Tanida I, Ikejima K and Watanabe S. (2011). Hepatic steatosis inhibits autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression. Biochem BiophysRes Commun 412: 618-625.
Jaffer FA, Vinegoni C, John MC, Aikawa E, Gold HK, Finn AV, Ntziachristos V, Libby P and Weissleder R. (2008). Real-time catheter molecular sensing of inflammation in proteolytically active atherosclerosis. Circulation 118: 1802-1809.
Ji G, Zhao X, Leng L, Liu P and Jiang Z. (2011). Comparison of dietary control and atorvastatin on high fat diet induced hepatic steatosis and hyperlipidemia in rats. Lipids Health Dis 10: 23.
Johnston TP. (2004). The P-407-induced murine models of dose-controlled hyperlipidemia and atherosclerosis. J Cardiovasc Pharmacol 43: 595-606.
Johnston TP. (2010). Poloxamer 407 as a general lipase inhibitor: its implications in lipid metabolism and atheroma formation in C57BL/6 mice. JPharm Pharmacol 62: 1807-1812.
Johnston TP, Nguyen LB, Chu WA and Shefer S. (2001). Potency of select statin drugs in a new mouse model of hyperlipidemia and atherosclerosis. Int J Pharm 229: 75-86.
Kim DE, Kim JY, Schellingerhout D, Shon SM, Jeong SW, Kim EJ and Kim WK. (2009). Molecular imaging of cathepsin B proteolytic enzyme activity reflects the inflammatory component of atherosclerotic pathology and can quantitatively demonstrate the antiatherosclerotic therapeutic effects of atorvastatin and glucosamine. Mol Imaging 8: 291-301.
Knight CG, Willenbrock F and Murphy G. (1992). A novel coumarin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases. FEBS Lett 296: 263-266.
Korolenko TA, Cherkanova MS, Tuzikov FV, Johnston TP, Tuzikova NA, Loginova VM and Kaledin, VI. (2011). Influence of atorvastatin on fractional and subfractional composition of serum lipoproteins and MMP activity in mice with Triton WR 1339-induced lipemia. J Pharm Pharmacol 65: 833-839.
Korolenko TA, Tuzikov FV, Cherkanova MS, Johnston TP, Tuzikova NA, Loginova VM, et al. (2012a). Influence of atorvastatin and carboxymethylated glucan on the serum lipoprotein profile and MMP activity of mice with poloxamer 407-induced lipemia. Can J Physiol Pharmacol 90: 141-153.
Korolenko TA, Tuzikov FV, Johnston TP, Tuzikova NA, Kisarova YaA, Zhanaeva SYa et al. (2012b). The influence of repeated administration of poloxamer 407 on serum lipoproteins and protease activity in mouse liver and heart. Can J Physiol Pharmacol 90: 1456-1468.
Lowry OH, Rosebrough NJ, Farr AL and Randall RJ. (1951). Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265-275.
Lutgens SP, Cleutjens KB, Daemen MJ and Heeneman S. Cathepsin cysteine proteases in cardiovascular disease. (2007). FASEB J 21: 3029-3041.
Müller AL, Hryshko LV and Dhalla NS. (2012). Extracellular and intracellular proteases in cardiac dysfunction due to ischemia-reperfusion injury. Int JCardiol. Feb 2012.
Ohira T, Diez Roux AV, Polak JF, Homma S, Iso H and Wasserman BA. (2012). Associations of anger, anxiety, and depressive symptoms with carotid arterial wall thickness: the multi-ethnic study of atherosclerosis. PsychosomMed 74: 517-525.
Palmer WK, Emeson EE and Johnston TP. (1998). Poloxamer 407-induced atherogenesis in the C57BL/6 mouse. Atherosclerosis 136: 115-123.
Peterson JT. (2006). The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. Cardiovasc Res 69: 677-687.
Qin Y and Shi GP. (2011). Cysteinyl cathepsins and mast cell proteases in the pathogenesis and therapeutics of cardiovascular diseases. Pharmacol Ther131: 338-350.
Reiser J, Adair B and Reinheckel T. (2010). Specialized roles for cysteine cathepsins in health and disease. J Clin Invest 120: 3421-34 31.
Rodgers RJ and Dalvi A. (1997). Anxiety, defence and the elevated plus-maze. Neurosci Biobehav Rev 21: 801-810.
Sjoberg S and Shi G-P. (2011). Cysteine protease cathepsins in atherosclerosis and abdominal aortic aneurysm. Clinic Rev Bone Miner Metab 9: 138-147.
Sun M, Chen M, Liu Y, Fukuoka M, Zhou K, Li G. et al. (2011). Cathepsin-L contributes to cardiac repair and remodelling post-infarction. Circulation 89: 374-383.
Tanaka H, Ishida T, Johnston TP, Yasuda T, Ueyama T, Kojima Y. et al. (2009). Role of endothelial lipase in plasma HDL levels in a murine model of hypertriglyceridemia. J Atheroscler Thromb 16: 327-338.
Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk, V and Turk, B. (2007). Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des 13 : 387-403.
Warren A, Benseler V, Cogger VC, Bertolino P and Le Couteur DG. (2011). The impact of poloxamer 407 on the ultrastructure of the liver and evidence for clearance by extensive endothelial and Kupffer cell endocytosis. ToxicolPathol 39: 390-397.
Wiederanders B, Kirschke H and Schaper S. (1986). The azocasein-urea-pepstatin assay discriminates between lysosomal proteinases. Biomed BiochimActa 45: 1477-1483.