Cardiac beta-defensins upregulate with a high fat diet and influence monocyte migration


Inflammation plays a central role in development of cardiovascular pathology, and enhanced understanding of the innate immune response will help direct novel therapeutic strategies to address heart disease. Host defense peptides (HDPs)—hereunder defensins—exhibit antimicrobial, chemotactic, tissue healing and other key biological properties. Beta-defensin expression in whole-heart-homogenate has been reported in different species, and plasma alpha-defensins have been associated with cardiovascular morbidity and mortality. Still, the role of defensins in cardiac pathophysiology remains widely undetermined. Here, we show that a subset of rat-beta-defensins (rBDs) is constitutively expressed in the myocardium, and that their gene-expression level is influenced by systemic exposure to inflammatory mediators (highfat-diet and lipopolysaccharide). Using synthetic analogues of select rBD peptides, we evaluated the antimicrobial activity of these HDPs against clinically relevant pathogens and their ability as immunoregulatory compounds. We found that an innate myocardial response that involves rBDs is activated by highfat-diet feeding in rats, and that these HDPs influence monocyte migration-findings that suggest the peptides responding to exogenous danger-signals, and act within the context of a myocardial “first-line-of-defense”.

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Linde, A. , Ross, C. , Blecha, F. , Lushington, G. and Melgarejo, T. (2013) Cardiac beta-defensins upregulate with a high fat diet and influence monocyte migration. Open Journal of Internal Medicine, 3, 81-94. doi: 10.4236/ojim.2013.32021.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Boman, H.G. (2003) Antibacterial peptides: Basic facts and emerging concepts. Journal of Internal Medicine, 254, 197-215. doi:10.1046/j.1365-2796.2003.01228.x
[2] Ganz, T. (2005) Defensins and other antimicrobial peptides: A historical perspective and an update. Combinato- rial Chemistry & High Throughput Screening, 8, 209-217. doi:10.2174/1386207053764594
[3] Linde, A., Mosier, D., Blecha, F. and Melgarejo, T. (2007) Innate immunity and inflammation-New frontiers in comparative cardiovascular pathology. Cardiovascular Research, 73, 26-36. doi:10.1016/j.cardiores.2006.08.009
[4] Davis, E.G., Sang, Y. and Blecha, F. (2004) Equine betadefensin-1: Full-length cDNA sequence and tissue expression. Veterinary Immunology and Immunopathology, l99, 127-132. doi:10.1016/j.vetimm.2003.12.010
[5] Garcia, J.R., Jaumann, F., Schulz, S., Krause, A., Rodriguez-Jimenez, J., Forssmann, U., Adermann, K., Kluver, E., Vogelmeier, C., Becker, D., Hedrich, R., Forssmann, W.G. and Bals, R. (2001) Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell and Tissue Research, 306, 257-264. doi:10.1007/s004410100433
[6] Jia, H.P., Schutte, B.C., Schudy, A., Linzmeier, R., Guthmiller, J.M., Johnson, G.K., Tack, B.F., Mitros, J.P., Rosenthal, A., Ganz, T. and McCray, P.B.J. (2001) Discovery of new human beta-defensins using a genomics-based approach. Gene, 263, 211-218. doi:10.1016/S0378-1119(00)00569-2
[7] Ma, D., Wang, R., Liao, W., Han, Z. and Liu, S. (2009) Identification and characterization of a novel antibacterial peptide, avian beta-defensin 2 from ducks. The Journal of Microbiology, 47, 610-618. doi:10.1007/s12275-009-0068-z
[8] Morrison, G., Kilanowski, F., Davidson, D. and Dorin, J. (2002) Characterization of the mouse beta defensin 1, Defb1, mutant mouse model. Infection and Immunity, 70, 3053-3060. doi:10.1128/IAI.70.6.3053-3060.2002
[9] Page, R.A. and Malik, A.N. (2003) Elevated levels of beta defensin-1 mRNA in diabetic kidneys of GK rats. Biochemical and Biophysical Research Communications, 310, 513-521. doi:10.1016/j.bbrc.2003.09.034
[10] Schutte, B.C. and McCray, P.B.J. (2002) Beta-defensins in lung host defense. Annual Review of Physiology, 64, 709-748. doi:10.1146/annurev.physiol.64.081501.134340
[11] Yang, Y., Wang, C., Zhao, Y. and Yu, X. (2009) Reindeer beta-defensin-1: Full-length cDNA cloning and tissue expression. Veterinary Immunology and Immunopathology, 131, 137-139. doi:10.1016/j.vetimm.2009.03.008
[12] Zhang, G., Wu, H., Shi, J., Ganz, T., Ross, C.R. and Blecha, F. (1998) Molecular cloning and tissue expression of porcine beta-defensin-1. FEBS Letters, 424, 37-40. doi:10.1016/S0014-5793(98)00134-3
[13] Barnathan, E.S., Raghunath, P.N., Tomaszewski, J.E., Ganz, T., Cines, D.B. and Higazi, A.-R. (1997) Immunohistochemical localization of defensin in human coronary vessels. American Journal of Pathology, 150, 1009-1020.
[14] Chavakis, T., Cines, D.B., Rhee, J.S., Liang, O.D., Schubert, U., Hammes, H.P., Higazi, A.A., Nawroth, P.P., Preissner, K. T. and Bdeir, K. (2004) Regulation of neovascularization by human neutrophil peptides (alpha-defen- sins): A link between inflammation and angiogenesis. The FASEB Journal, 18, 1306-1308. doi:10.1096/fj.03-1009fje
[15] Kougias, P., Chai, H., Lin, P.H., Yao, Q., Lumsden, A.B. and Chen, C. (2005) Defensins and cathelicidins: Neutrophil peptides with roles in inflammation, hyperlipidemia and atherosclerosis. Journal of Cellular and Molecular Medicine, 9, 3-10. doi:10.1111/j.1582-4934.2005.tb00332.x
[16] Lopez-Bermejo, A., Chico-Julia, B., Castro, A., Recasens, M., Esteve, E., Biarnes, J., Casamitjana, R., Ricart, W. and Fernandez-Real, J.M. (2007) Alpha defensins 1, 2, and 3: Potential roles in dyslipidemia and vascular dysfunction in humans. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 1166-1171. doi:10.1161/ATVBAHA.106.138594
[17] Doggrell, S.A. (2005) Recent advances in heart research. Drug News & Perspectives, 18, 58-72.
[18] Libby, P., Ridker, P.M. and Maseri, A. (2002) Inflammation and atherosclerosis. Circulation, 105, 1135-1143. doi:10.1161/hc0902.104353
[19] Rader, D.J. and Daugherty, A. (2008) Translating molecular discoveries into new therapies for atherosclerosis. Nature, 451, 904-913. doi:10.1038/nature06796
[20] Baumgarten, G., Knuefermann, P., Nozaki, N., Sivasubramanian, N., Mann, D.L. and Vallejo, J.G. (2001) In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: The role of toll-like receptor-4. The Journal of Infectious Diseases, 183, 1617- 1624. doi:10.1086/320712
[21] Thompson, J.D., Higgins, D.G. and Gibson, T.J. (1994) CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Research, 22, 4673-4680. doi:10.1093/nar/22.22.4673
[22] Sanchez, R. and Sali, A. (2000) Comparative protein structure modeling. Introduction and practical examples with modeller. Methods in Molecular Biology, 143, 97- 129. doi:10.1385/1-59259-368-2:97
[23] Wiegand, I., Hilpert, K. and Hancock, R.E. (2008) Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nature Protocols, 3, 163-175. doi:10.1038/nprot.2007.521
[24] Wikler, M.A., Cockerill, F.R., Craig, W.A., Dudley, M.N., Eliopoulos, G.M., Hecht, D.W., Hindler, J.F., Ferraro, M.J., Swenson, J.M., Low, D.E., Sheehan, D.J., Tenover, F.C., Turnidge, J.D., Weinstein, M.P. and Zimmer, B.L.. (2006) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-seventh edition. Clinical and Laboratory Standards Institute Report No. M7-A7.
[25] Linde, A., Lushington, G.H., Blecha, F. and Melgarejo, T. (2008) Rat cardiomyocytes express a classical epithelial beta-defensin. American Journal of Animal and Veterinary Sciences, 3, 1-6. doi:10.3844/ajavsp.2008.1.6
[26] Branger, S., Casalta, J.P., Habib, G., Collard, F. and Raoult, D. (2005) Escherichia coli endocarditis: Seven new cases in adults and review of the literature. European Journal of Clinical Microbiology & Infectious Diseases, 24, 537- 541. doi:10.1007/s10096-005-1379-6
[27] Naber, C.K. (2008) Future strategies for treating Staphylococcus aureus bloodstream infections. Clinical Microbiology and Infection, 14, 26-34. doi:10.1111/j.1469-0691.2008.01924.x
[28] Spyrou, N., Anderson, M. and Foale, R. (1997) Listeria endocarditis: Current management and patient outcomeworld literature review. Heart, 77, 380-383.
[29] Knuefermann, P., Nemoto, S., Baumgarten, G., Misra, A., Sivasubramanian, N., Carabello, B.A. and Vallejo, J.G. (2002) Cardiac inflammation and innate immunity in septic shock: Is there a role for toll-like receptors? Chest, 121, 1329-1336. doi:10.1378/chest.121.4.1329
[30] Ross, R. (1993) The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature, 362, 801-809. doi:10.1038/362801a0
[31] Knuefermann, P., Sakata, Y., Baker, J.S., Huang, C.H., Sekiguchi, K., Hardarson, H.S., Takeuchi, O., Akira, S. and Vallejo, J.G. (2004) Toll-like receptor 2 mediates Staphylococcus aureus-induced myocardial dysfunction and cytokine production in the heart. Circulation, 110, 3693- 3698. doi:10.1161/01.CIR.0000143081.13042.04
[32] Matzinger, P. (2007) Friendly and dangerous signals: Is the tissue in control? Nature Immunology, 8, 11-13. doi:10.1038/ni0107-11
[33] Raz, E. (2007) Organ-specific regulation of innate immunity. Nature Immunology, 8, 3-4. doi:10.1038/ni0107-3
[34] Stryjewski, M.E., Hall, R.P., Chu, V.H., Kanafani, Z.A., O’Riordan, W.D., Weinstock, M.S., Stienecker, R.S., Streilein, R., Dorschner, R.A., Fowler, V.G.J., Corey, G.R. and Gallo, R.L. (2007) Expression of antimicrobial peptides in the normal and involved skin of patients with infective cellulitis. The Journal of Infectious Diseases, 196, 1425- 1430. doi:10.1086/522630
[35] Abedin, A., Mohammed, I., Hopkinson, A. and Dua, H.S. (2008) A novel antimicrobial peptide on the ocular surface shows decreased expression in inflammation and infection. Investigative Ophthalmology & Visual Science, 49, 28-33. doi:10.1167/iovs.07-0645
[36] Selsted, M.E. and Ouellette, A.J. (2005) Mammalian defensins in the antimicrobial immune response. Nature Immunology?, 6, 551-557.
[37] Fehlbaum, P., Rao, M., Zasloff, M. and Anderson, G.M. (2000) An essential amino acid induces epithelial betadefensin expression. Proceedings of the National Academy of Sciences of the United States of America, 97, 12723-12728. doi:10.1073/pnas.220424597
[38] Bdeir, K., Cane, W., Canziani, G., Chaiken, I., Weisel, J., Koschinsky, M.L., Lawn, R.M., Bannerman, P.G., Sachais, B.S., Kuo, A., Hancock, M.A., Tomaszewski, J., Raghunath, P.N., Ganz, T., Higazi, A.A. and Cines, D.B. (1999) Defensin promotes the binding of lipoprotein (a) to vascular matrix. Blood, 94, 2007-2019.
[39] Higazi, A.A., Lavi, E., Bdeir, K., Ulrich, A.M., Jamieson, D.G., Rader, D.J., Usher, D.C., Kane, W., Ganz, T. and Cines, D.B. (1997) Defensin stimulates the binding of lipoprotein (a) to human vascular endothelial and smooth muscle cells. Blood, 89, 4290-4298.
[40] Higazi, A.A., Nassar, T., Ganz, T., Rader, D.J., Udassin, R., Bdeir, K., Hiss, E., Sachais, B.S., Williams, K.J., Leitersdorf, E. and Cines, D.B. (2000) The alpha-defensins stimulate proteoglycan-dependent catabolism of lowdensity lipoprotein by vascular cells: A new class of inflammatory apolipoprotein and a possible contributor to atherogenesis. Blood, 96, 1393-1398.
[41] Joseph, G., Tarnow, L., Astrup, A.S., Hansen, T.K., Parving, H.H., Flyvbjerg, A. and Frystyk, J. (2008) Plas- ma alpha-defensin is associated with cardiovascular morbidity and mortality in type 1 diabetic patients. The Journal of Clinical Endocrinology & Metabolism, 93, 1470- 1475. doi:10.1210/jc.2007-1910
[42] Christensen, H.M., Frystyk, J., Faber, J., Schou, M., Flyvbjerg, A., Hildebrandt, P., Raymond, I., Klausen, T.W. and Kistorp, C. (2012) Alpha-defensins and outcome in patients with chronic heart failure. European Journal of Heart Failure, 14, 387-394. doi:10.1093/eurjhf/hfs021
[43] Higazi, A.A., Barghouti, I.I. and Abu-Much, R. (1995) Identification of an inhibitor of tissue-type plasminogen activator-mediated fibrinolysis in human neutrophils. A role for defensin. Journal of Biological Chemistry, 270, 9472-9477.doi:10.1074/jbc.270.16.9472
[44] Nassar, H., Lavi, E., Akkawi, S., Bdeir, K., Heyman, S. N., Raghunath, P.N., Tomaszewski, J. and Higazi, A.A. (2007) Alpha-defensin: Link between inflammation and atherosclerosis. Atherosclerosis, 194, 452-457. doi:10.1016/j.atherosclerosis.2006.08.046
[45] Panyutich, A.V., Panyutich, E.A., Krapivin, V.A., Baturevich, E.A. and Ganz, T. (1993) Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis. The Journal of Laboratory and Clinical Medicine, 122, 202-207.
[46] Ashitani, J., Mukae, H., Hiratsuka, T., Nakazato, M., Kumamoto, K. and Matsukura, S. (2002) Elevated levels of alpha-defensins in plasma and BAL fluid of patients with active pulmonary tuberculosis. Chest, 121, 519-526. doi:10.1378/chest.121.2.519
[47] Hancock, R.E. (2001) Cationic peptides: Effectors in innate immunity and novel antimicrobials. The Lancet Infectious Disease, 1, 156-164. doi:10.1016/S1473-3099(01)00092-5
[48] Merle, U., Fein, E., Gehrke, S.G., Stremmel, W. and Kulaksiz, H. (2007) The iron regulatory peptide hepcidin is expressed in the heart and regulated by hypoxia and inflammation. Endocrinology, 148, 2663-2668. doi:10.1210/en.2006-1331
[49] Karapetyan, A.V., Klyachkin, Y.M., Selim, S., Sunkara, M., Ziada, K.M., Cohen, D.A., Zuba-Surma, E.K., Ratajczak, J., Smyth, S.S., Ratajczak, M.Z., Morris, A.J. and Abdel-Latif, A. (2013) Bioactive lipids and cationic antimicrobial peptides as new potential regulators for trafficking of bone marrow-derived stem cells in patients with acute myocardial infarction. Stem Cells and Development, 22, 1645-1656. doi:10.1089/scd.2012.0488
[50] Salonen, J.K., Pirskanen, M., Haarus, J., Tuomainen, T.P. and Yunus, F. (2007) Method for detecting the risk of cardiovascular diseases such as acute myocardial infarction and coronary heart disease by analyzing defensin. US Patent No. US2007/0299025 A1.
[51] Apostolakis, S., Lip, G.Y. and Shantsila, E. (2010) Monocytes in heart failure: Relationship to a deteriorating immune overreaction or a desperate attempt for tissue repair? Cardiovascular Research, 85, 649-660. doi:10.1093/cvr/cvp327
[52] Cani, P.D., Amar, J., Iglesias, M.A., Poggi, M., Knauf, C., Bastelica, D., Neyrinck, A.M., Fava, F., Tuohy, K.M., Chabo, C., Waget, A., Delmee, E., Cousin, B., Sulpice, T., Chamontin, B., Ferrieres, J., Tanti, J.F., Gibson, G.R., Casteilla, L., Delzenne, N.M., Alessi, M.C. and Burcelin, R. (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 56, 1761-1772. doi:10.2337/db06-1491
[53] Shi, H., Kokoeva, M.V., Inouye, K., Tzameli, I., Yin, H. and Flier, J.S. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of Clinical Investigation, 116, 3015-3025. doi:10.1172/JCI28898
[54] Frantz, S., Kobzik, L., Kim, Y.D., Fukazawa, R., Medzhitov, R., Lee, R.T. and Kelly, R.A. (1999) Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. The Journal of Clinical Investigation, 104, 271-280. doi:10.1172/JCI6709
[55] Frantz, S., Kelly, R.A. and Bourcier, T. (2001) Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. Journal of Biological Chemistry, 276, 5197-5203. doi:10.1074/jbc.M009160200
[56] Shishido, T., Nozaki, N., Yamaguchi, S., Shibata, Y., Nitobe, J., Miyamoto, T., Takahashi, H., Arimoto, T., Maeda, K., Yamakawa, M., Takeuchi, O., Akira, S., Takeishi, Y. and Kubota, I. (2003) Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation, 108, 2905-2910. doi:10.1161/01.CIR.0000101921.93016.1C
[57] Tavener, S.A., Long, E.M., Robbins, S.M., McRae, K.M., Van Remmen, H. and Kubes, P. (2004) Immune cell Tolllike receptor 4 is required for cardiac myocyte impairment during endotoxemia. Circulation Research, 95, 700- 707. doi:10.1161/01.RES.0000144175.70140.8c
[58] Kanters, E., Pasparakis, M., Gijbels, M.J., Vergouwe, M. N., Partouns-Hendriks, I., Fijneman, R.J., Clausen, B.E., Forster, I., Kockx, M.M., Rajewsky, K., Kraal, G., Hofker, M.H. and de Winther, M.P. (2003) Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. The Journal of Clinical Investigation, 112, 1176-1185. doi:10.1172/JCI18580
[59] Lourenzoni, M.R., Namba, A.M., Caseli, L., Degreve, L. and Zaniquelli, M.E. (2007) Study of the interaction of human defensins with cell membrane models: Relationships between structure and biological activity. The Journal of Physical Chemistry B, 111, 11318-11329. doi:10.1021/jp067127g
[60] Taylor, K., Barran, P.E. and Dorin, J.R. (2008) Structure-activity relationships in beta-defensin peptides. Pep- tide Science, 90, 1-7. doi:10.1002/bip.20900
[61] Wu, Z., Hoover, D.M., Yang, D., Boulegue, C., San- tamaria, F., Oppenheim, J.J., Lubkowski, J. and Lu, W. (2003) Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human beta-defensin 3. Proceedings of the National Academy of Sciences of the United States of America, 100, 8880-8885. doi:10.1073/pnas.1533186100
[62] Territo, M.C., Ganz, T., Selsted, M.E. and Lehrer, R. (1989) Monocyte-chemotactic activity of defensins from human neutrophils. The Journal of Clinical Investigation, 84, 2017-2020. doi:10.1172/JCI114394
[63] Grutkoski, P.S., Graeber, C.T., Lim, Y.P., Ayala, A. and Simms, H.H. (2003) Alpha-defensin 1 (human neutrophil protein 1) as an antichemotactic agent for human polymorphonuclear leukocytes. Antimicrobial Agents and Chemotherapy, 47, 2666-2668. doi:10.1128/AAC.47.8.2666-2668.2003
[64] Soruri, A., Grigat, J., Forssmann, U., Riggert, J. and Zwirner, J. (2007) Beta-defensins chemoattract macro- phages and mast cells but not lymphocytes and dendritic cells: CCR6 is not involved. European Journal of Immunology, l37, 2474-2486.doi:10.1002/eji.200737292
[65] Rohrl, J., Yang, D., Oppenheim, J.J. and Hehlgans, T. (2010) Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2. The Journal of Immunology, 184, 6688-6694. doi:10.4049/jimmunol.0903984
[66] de Beer, F.C., Baltz, M.L., Munn, E.A., Feinstein, A., Taylor, J., Bruton, C., Clamp, J.R. and Pepys, M.B. (1982) Isolation and characterization of C-reactive protein and serum amyloid P component in the rat. Immunology, 45, 55-70.
[67] Garcia, J.R., Krause, A., Schulz, S., Rodriguez-Jimenez, F.J., Kluver, E., Adermann, K., Forssmann, U., Frimpong-Boateng, A., Bals, R. and Forssmann, W.G. (2001) Human beta-defensin 4: A novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity. The FASEB Journal, 15, 1819-1821. doi:10.1096/fj.00-0865fje

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