Share This Article:

C5L2 Deficiency Enhances Development of Atherosclerosis in ApoE Knockout Mice

Full-Text HTML XML Download Download as PDF (Size:1905KB) PP. 61-74
DOI: 10.4236/cm.2015.61007    2,905 Downloads   3,331 Views   Citations

ABSTRACT

Background: The complement system is important in development of atherosclerosis via regulation of lipid and glucose metabolism as well as inflammation. Aim: The aim of the present study was to further analyze the contribution of C5L2 to the development of atherosclerosis. We proposed that, with DIO feeding, C5L2 deficiency would promote a phenotype that encourages atherosclerosis development. Coupled to ApoE deficiency, double knockout (2KO) mice would show exacerbated atherosclerotic plaque formation. Methods: First, Wildtype (WT) and C5L2-/-(C5L2KO) and subsequently, ApoE-/-(ApoEKO) and C5L2/ApoE double knockout mice were placed on diets inducing obesity (DIO) or standard chow diet for 12 - 15 weeks. Plasma lipids, glucose, cytokines and hepatic glycogen and lipid contents, mRNA levels and enzyme activities and atherosclerotic plaque size were measured. Results: C5L2KO had increased hepatic glucose oxidation (+90%, p < 0.001), reduced liver glycogen content on chow diet (-34%, p < 0.05) but increased with DIO (+51%, p < 0.05) vs WT. Glucose clearance was delayed in C5L2/ApoE-2KO vs ApoEKO mice with chow (p < 0.0001) and DIO diet (p = 0.0026). C5L2KO mice had increased hepatic lipid content and fatty acid synthesis but decreased lipid oxidation vs WT. Plasma cholesterol was further elevated in C5L2/ApoE-2KO vs ApoEKO with DIO feeding (p < 0.05). Hepatic cytokine expression was increased in C5L2KO mice compared to WT mice. Atherosclerotic plaque size was increased in C5L2/ ApoE-2KO mice compared with apoEKO on chow (p < 0.05) and DIO regimen (p < 0.001). Conclusions: C5L2 disruption worsens glucose and lipid metabolism, increases hepatic and circulating inflammation, and aggravates atherosclerosis.

Cite this paper

Liu, Y. , Fisette, A. , Lapointe, M. and Cianflone, K. (2015) C5L2 Deficiency Enhances Development of Atherosclerosis in ApoE Knockout Mice. Chinese Medicine, 6, 61-74. doi: 10.4236/cm.2015.61007.

References

[1] Glass, C. and Witztum, J. (2001) Atherosclerosis. The Road Ahead. Cell, 104, 503-516.
http://dx.doi.org/10.1016/S0092-8674(01)00238-0
[2] Packard, R.R., Lichtman, A.H. and Libby, P. (2009) Innate and Adaptive Immunity in Atherosclerosis. Seminars in Immunopathology, 31, 5-22.
http://dx.doi.org/10.1007/s00281-009-0153-8
[3] Libby, P., Ridker, P.M. and Hansson, G.K. (2011) Progress and Challenges in Translating the Biology of Atherosclerosis. Nature, 473, 317-325.
http://dx.doi.org/10.1038/nature10146
[4] Hess, K. (2015) The Vulnerable Blood. Coagulation and Clot Structure in Diabetes Mellitus. Hamostaseologie, 35, 25-33.
http://dx.doi.org/10.5482/HAMO-14-09-0039
[5] Hertle, E., Stehouwer, C.D. and van Greevenbroek, M.M. (2014) The Complement System in Human Cardiometabolic Disease. Molecular Immunology, 61, 135-148.
http://dx.doi.org/10.1016/j.molimm.2014.06.031
[6] Onat, A., Can, G., Rezvani, R. and Cianflone, K. (2011) Complement C3 and Cleavage Products in Cardiometabolic Risk. Clinica Chimica Acta, 412, 1171-1179.
http://dx.doi.org/10.1016/j.cca.2011.03.005
[7] Gauvreau, D., Gupta, A., Fisette, A., Tom, F.Q. and Cianflone, K. (2013) Deficiency of C5L2 Increases Macrophage Infiltration and Alters Adipose Tissue Function in Mice. PLoS One, 8, e60795.
http://dx.doi.org/10.1371/journal.pone.0060795
[8] Kalant, D., et al. (2014) C5L2 Is a Functional Receptor for Acylation-Stimulating Protein. The Journal of Biological Chemistry, 280, 23936-23944.
http://dx.doi.org/10.1074/jbc.M406921200
[9] Kalant, D., et al. (2003) Thechemoattractant Receptor-Like Protein C5L2 Binds the C3a des-Arg77/acylation-Stimulating Protein. The Journal of Biological Chemistry, 278, 11123-11129. http://dx.doi.org/10.1074/jbc.M206169200
[10] Murray, I., Sniderman, A.D., Havel, P.J. and Cianflone, K. (1999) Acylation Stimulating Protein (ASP) Detciency Alters Postprandial and Adipose Tissue Metabolism in Male Mice. The Journal of Biological Chemistry, 274, 36219-36225.
http://dx.doi.org/10.1074/jbc.274.51.36219
[11] Paglialunga, S., Schrauwen, P., Roy, C., Moonen-Kornips, E., Lu, H., Hesselink, M.K.C., Deshaies, Y., Richard, D. and Cianflone, K. (2007) Reduced Adipose Tissue Triglyceride Synthesis and Increased Muscle Fatty Acid Oxidation in C5L2 Knockout Mice. Journal of Endocrinology, 194, 293-304.
http://dx.doi.org/10.1677/JOE-07-0205
[12] Roy, C., Paglialunga, S., Schaart, G., Moonen-Kornips, E., Meex, R.C., Phielix, E., et al. (2013) Relationship of C5L2 Receptor to Skeletal Muscle Substrate Utilization. PLoS ONE, 8, e57494.
http://dx.doi.org/10.1371/journal.pone.0057494
[13] Fisette, A., Munkonda, M.N., Oikonomopoulou, K., Paglialunga, S., Lambris, J.D. and Cianflone, K. (2013) C5L2 Receptor Disruption Enhances the Development of Diet-Induced Insulin Resistance in Mice. Immunobiology, 218, 127-133.
http://dx.doi.org/10.1016/j.imbio.2012.04.001
[14] Monk, P.N., Scola, A.M., Madala, P. and Fairlie, D.P. (2007) Function, Structure and Therapeutic Potential of Complement C5a Receptors. British Journal of Pharmacology, 152, 429-448. http://dx.doi.org/10.1038/sj.bjp.0707332
[15] Hsu, W.C., Yang, F.C., Lin, C.H., Hsieh, S.L. and Chen, N.J. (2014) C5L2 Is Required for C5a-Triggered Receptor Internalization and ERK Signaling. Cellular Signalling, 26, 1409-1419.
http://dx.doi.org/10.1016/j.cellsig.2014.02.021
[16] Wang, R., Lu, B., Gerard, C. and Gerard, N.P. (2013) Disruption of the Complement Anaphylatoxin Receptor C5L2 Exacerbates Inflammation in Allergic Contact Dermatitis. Journal of Immunology, 191, 4001-4009.
http://dx.doi.org/10.4049/jimmunol.1301626
[17] Speid, W.S., Kastl, S.P., Hutter, R., Katsaros, K.M., Kaun, C., Bauriedel, G., Maurer, G., Huber, K., Badimon, J.J. and Wojta, J. (2011) The Complement Component C5a Is Present in Human Coronary Lesions in Vivo and Induces the Expression of MMP-1 and MMP-9 in Human Macrophages in Vitro. FASEB Journal, 25, 35-44.
http://dx.doi.org/10.1096/fj.10-156083
[18] Speidl, W.S., Exner, M., Amighi, J., Kastl, S.P., Zorn, G., Maurer, G., et al. (2005) Complement Component C5a Predicts Future Cardiovascular Events in Patients with Advanced Atherosclerosis. European Heart Journal, 26, 2294-2299.
http://dx.doi.org/10.1093/eurheartj/ehi339
[19] Wezel, A., de Vries, M.R., Maxime Lagraauw, H., Foks, A.C., Kuiper, J., Quax, P.H.A. and Bot, I. (2014) Complement Factor C5a Induces Atherosclerotic Plaque Disruptions. Journal of Cellular and Molecular Medicine, 18, 2020-2030.
http://dx.doi.org/10.1111/jcmm.12357
[20] Clarke, M.C., Figg, N., Maguire, J.J., Davenport, A.P., Goddard, M., Littlewood, T.D. and Bennett, M.R. (2006) Apoptosis of Vascular Smooth Muscle Cells Induces Features of Plaque Vulnerability in Atherosclerosis. Nature Medicine, 12, 1075-1080.
http://dx.doi.org/10.1038/nm1459
[21] Bieghs, V., Rensen, P.C., Hofker, M.H. and Shiri-Sverdlov, R. (2012) NASH and Atherosclerosis Are Two Aspects of a Shared Disease: Central Role for Macrophages. Atherosclerosis, 220, 287-293.
http://dx.doi.org/10.1016/j.atherosclerosis.2011.08.041
[22] Joven, J., Rull, A., Ferré, N., Escolà-Gil, J.C., Marsillach, J., Coll, B., et al. (2007) The Results in Rodent Models of Atherosclerosis Are Not Interchangeable: The Influence of Diet and Strain. Atherosclerosis, 195, e85-e92.
http://dx.doi.org/10.1016/j.atherosclerosis.2007.06.012
[23] Tous, M., Ferre, N., Camps, J., Riu, F. and Joven, J. (2005) Feeding Apolipoprotein E-Knockout Mice with Cholesterol and Fat Enriched Diets May Be a Model of Non-Alcoholic Steatohepatitis. Molecular and Cellular Biochemistry, 268, 53-58.
http://dx.doi.org/10.1007/s11010-005-2997-0
[24] Manthey, H.D., Thomas, A.C., Shiels, I.A., Zernecke, A., Woodruff, T.M., Rolfe, B. and Taylor, S.M. (2011) Complement C5a Inhibition Reduces Atherosclerosis in ApoE-/-Mice. FASEB Journal, 25, 2447-2455.
http://dx.doi.org/10.1096/fj.10-174284
[25] Roy, C., Paglialunga, S., Fisette, A., Schrauwen, P., Moonen-Kornips, E., St-Onge, J., et al. (2008) Shift in Metabolic Fuel in Acylation-Stimulating Protein-Deficient Mice Following a High-Fat Diet. American Journal of Physiology— Endocrinology and Metabolism, 294, E1051-E1059. http://dx.doi.org/10.1152/ajpendo.00689.2007
[26] Murray, I., Parker, R.A., Kirchgessner, T.G., Tran, J., Zhang, Z.J., Westerlund, J. and Cianflone, K. (1997) Functional Bioactive Recombinant Acylation Stimulating Protein Is Distinct from C3a Anaphylatoxin. Journal of Lipid Research, 38, 2492-2501.
[27] Marcus, F. and Hosey, M.M. (1980) Purification and Properties of Liver Fructose 1,6-Bisphosphatase from C57Bl-KsJ Normal and Diabetic Mice. Journal of Biological Chemistry, 255, 2481-2486.
[28] Festuccia, W.T., Blanchard, P.G., Turcotte, V., Laplante, M., Sariahmetoglu, M., Brindley, D.N., et al. (2009) The PPARγ Agonist Rosiglitazone Enhances Rat Brown Adipose Tissue Lipogenesis from Glucose without Altering Glucose Uptake. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 296, R1327-R1335. http://dx.doi.org/10.1152/ajpregu.91012.2008
[29] Bustin, S.A., Benes, V., Garson, J.A., Hellemans, J., Huggett, J., Kubista, M., et al. (2009) The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR Experiments. Clinical Chemistry, 55, 611-622.
http://dx.doi.org/10.1373/clinchem.2008.112797
[30] Choi, C.S., Savage, D.B., Kulkarni, A., Yu, X.X., Liu, Z.X., Morino, K., et al. (2007) Suppression of Diacylglycerol Acyltransferase-2 (DGAT2), but Not DGAT1, with Antisense Oligonucleotides Reverses Diet-Induced Hepatic Steatosis and Insulin Resistance. Journal of Biological Chemistry, 282, 22678-22688.
http://dx.doi.org/10.1074/jbc.M704213200
[31] Monetti, M., Levin, M.C., Watt, M.J., Sajan, M.P., Marmor, S., Hubbard, B.K., et al. (2014) Dissociation of Hepatic Steatosis and Insulin Resistance in Mice Overexpressing DGAT in the Liver. Cell Metabolism, 6, 69-78.
http://dx.doi.org/10.1016/j.cmet.2007.05.005
[32] DeFronzo, R.A. (2010) Insulin Resistance, Lipotoxicity, Type 2 Diabetes and Atherosclerosis: The Missing Links. The Claude Bernard Lecture 2009. Diabetologia, 53, 1270-1287.
http://dx.doi.org/10.1007/s00125-010-1684-1
[33] Targher, G. and Arcaro, G. (2007) Non-Alcoholic Fatty Liver Disease and Increased Risk of Cardiovascular Disease. Atherosclerosis, 191, 235-240.
http://dx.doi.org/10.1016/j.atherosclerosis.2006.08.021
[34] Tous, M., Ferré, N., Rull, A., Marsillach, J., Coll, B., Alonso-Villaverde, C., Camps, J. and Joven, J. (2006) Dietary Cholesterol and Differential Monocyte Chemoattractant Protein-1 Gene Expression in Aorta and Liver of Apo E-Deficient Mice. Biochemical and Biophysical Research Communications, 340, 1078-1084.
http://dx.doi.org/10.1016/j.bbrc.2005.12.109
[35] Samstad, E.O., Niyonzima, N., Nymo, S., Aune, M.H., Ryan, L., Bakke, S.S., et al. (2014) Cholesterol Crystals Induce Complement-Dependent Inflammasome Activation and Cytokine Release. Journal of Immunology, 192, 2837-2845.
http://dx.doi.org/10.4049/jimmunol.1302484
[36] Kleemann, R., Verschuren, L., van Erk, M.J., Nikolsky, Y., Cnubben, N.H.P., Verheij, E.R., et al. (2007) Atherosclerosis and Liver Inflammation Induced by Increased Dietary Cholesterol Intake: A Combined Transcriptomics and Metabolomics Analysis. Genome Biology, 8, R200. http://dx.doi.org/10.1186/gb-2007-8-9-r200
[37] Persson, L., Borén, J., Robertson, A.K.L., Wallenius, V., Hansson, G.K. and Pekna, M. (2004) Lack of Complement Factor C3, but Not Factor B, Increases Hyperlipidemia and Atherosclerosis in Apolipoprotein E-/-Low-Density Lipoprotein Receptor-/-Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 1062-1067.
http://dx.doi.org/10.1161/01.ATV.0000127302.24266.40
[38] Poursharifi, P., Lapointe, M., Pétrin, D., Devost, D., Gauvreau, D., Hébert, T.E. and Cianflone, K. (2013) C5L2 and C5aR Interaction in Adipocytes and Macrophages: Insights into Adipoimmunology. Cellular Signalling, 25, 910-918.
http://dx.doi.org/10.1016/j.cellsig.2012.12.010
[39] Oksjoki, R., Laine, P., Helske, S., Vehmaan-Kreula, P., Mäyränpää, M.I., Gasque, P., et al. (2007) Receptors for the Anaphylatoxins C3a and C5a in Human Atherosclerotic Coronary Plaques. Atherosclerosis, 195, 90-99.
http://dx.doi.org/10.1016/j.atherosclerosis.2006.12.016
[40] Shagdarsuren, E., Bidzhekov, K., Mause, S.F., Simsekyilmaz, S., Polakowski, T., Hawlisch, H., et al. (2010) C5a Receptor Targeting in Neointima Formation after Arterial Injury in Atherosclerosis-Prone Mice. Circulation, 122, 1026-1036.
http://dx.doi.org/10.1161/CIRCULATIONAHA.110.954370

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.