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BMC Medicine
Published in: BMC Medicine 1/2012

Open Access 01-12-2012 | Research article

Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy

Authors: Machender R Kandadi, Xuejun Yu, Arthur E Frankel, Jun Ren

Published in: BMC Medicine | Issue 1/2012

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Abstract

Background

Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction.

Methods

Wild type (WT) and cardiac-specific catalase overexpression mice were challenged with lethal toxin (2 μg/g, intraperotineally (i.p.)). Cardiomyocyte contractile and intracellular Ca2+ properties were assessed 18 h later using an IonOptix edge-detection system. Proteasome function was assessed using chymotrypsin-like and caspase-like activities. GFP-LC3 puncta and Western blot analysis were used to evaluate autophagy and protein ubiquitination.

Results

Lethal toxin exposure suppressed cardiomyocyte contractile function (suppressed peak shortening, maximal velocity of shortening/re-lengthening, prolonged duration of shortening/re-lengthening, and impaired intracellular Ca2+ handling), the effects of which were alleviated by catalase. In addition, lethal toxin triggered autophagy, mitochondrial and ubiquitin-proteasome defects, the effects of which were mitigated by catalase. Pretreatment of cardiomyocytes from catalase mice with the autophagy inducer rapamycin significantly attenuated or ablated catalase-offered protection against lethal toxin-induced cardiomyocyte dysfunction. On the other hand, the autophagy inhibitor 3-MA ablated or significantly attenuated lethal toxin-induced cardiomyocyte contractile anomalies.

Conclusions

Our results suggest that catalase is protective against anthrax lethal toxin-induced cardiomyocyte contractile and intracellular Ca2+ anomalies, possibly through regulation of autophagy and mitochondrial function.
Appendix
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Literature
1.
Borio L, Frank D, Mani V, Chiriboga C, Pollanen M, Ripple M, Ali S, DiAngelo C, Lee J, Arden J, Titus J, Fowler D, O'Toole T, Masur H, Bartlett J, Inglesby T: Death due to bioterrorism-related inhalational anthrax: report of 2 patients. JAMA. 2001, 286: 2554-2559. 10.1001/jama.286.20.2554.CrossRefPubMed
2.
Fraser CM, Dando MR: Genomics and future biological weapons: the need for preventive action by the biomedical community. Nat Genet. 2001, 29: 253-256. 10.1038/ng763.CrossRefPubMed
3.
Holty JE, Bravata DM, Liu H, Olshen RA, McDonald KM, Owens DK: Systematic review: a century of inhalational anthrax cases from 1900 to 2005. Ann Intern Med. 2006, 144: 270-280.CrossRefPubMed
4.
Moayeri M, Leppla SH: The roles of anthrax toxin in pathogenesis. Curr Opin Microbiol. 2004, 7: 19-24. 10.1016/j.mib.2003.12.001.CrossRefPubMed
5.
Cui X, Moayeri M, Li Y, Li X, Haley M, Fitz Y, Correa-Araujo R, Banks SM, Leppla SH, Eichacker PQ: Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats. Am J Physiol Regul Integr Comp Physiol. 2004, 286: R699-709. 10.1152/ajpregu.00593.2003.CrossRefPubMed
6.
Rossi CA, Ulrich M, Norris S, Reed DS, Pitt LM, Leffel EK: Identification of a surrogate marker for infection in the African green monkey model of inhalation anthrax. Infect Immun. 2008, 76: 5790-5801. 10.1128/IAI.00520-08.CrossRefPubMedPubMedCentral
7.
Moayeri M, Leppla SH: Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol Aspects Med. 2009, 30: 439-455. 10.1016/j.mam.2009.07.003.CrossRefPubMedPubMedCentral
8.
Bradley KA, Mogridge J, Mourez M, Collier RJ, Young JA: Identification of the cellular receptor for anthrax toxin. Nature. 2001, 414: 225-229. 10.1038/n35101999.CrossRefPubMed
9.
Scobie HM, Rainey GJ, Bradley KA, Young JA: Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. Proc Natl Acad Sci USA. 2003, 100: 5170-5174. 10.1073/pnas.0431098100.CrossRefPubMedPubMedCentral
10.
Moayeri M, Martinez NW, Wiggins J, Young HA, Leppla SH: Mouse susceptibility to anthrax lethal toxin is influenced by genetic factors in addition to those controlling macrophage sensitivity. Infect Immun. 2004, 72: 4439-4447. 10.1128/IAI.72.8.4439-4447.2004.CrossRefPubMedPubMedCentral
11.
Barakat LA, Quentzel HL, Jernigan JA, Kirschke DL, Griffith K, Spear SM, Kelley K, Barden D, Mayo D, Stephens DS, Popovic T, Marston C, Zaki SR, Guarner J, Shieh WJ, Carver HW, Meyer RF, Swerdlow DL, Mast EE, Hadler JL: Fatal inhalational anthrax in a 94-year-old Connecticut woman. JAMA. 2002, 287: 863-868. 10.1001/jama.287.7.863.CrossRefPubMed
12.
Sweeney DA, Cui X, Solomon SB, Vitberg DA, Migone TS, Scher D, Danner RL, Natanson C, Subramanian GM, Eichacker PQ: Anthrax lethal and edema toxins produce different patterns of cardiovascular and renal dysfunction and synergistically decrease survival in canines. J Infect Dis. 2010, 202: 1885-1896. 10.1086/657408.CrossRefPubMedPubMedCentral
13.
Lawrence WS, Marshall JR, Zavala DL, Weaver LE, Baze WB, Moen ST, Whorton EB, Gourley RL, Peterson JW: Hemodynamic effects of anthrax toxins in the rabbit model and the cardiac pathology induced by lethal toxin. Toxins (Basel). 2011, 3: 721-736.CrossRef
14.
Kandadi MR, Hua Y, Ma H, Li Q, Kuo SR, Frankel AE, Ren J: Anthrax lethal toxin suppresses murine cardiomyocyte contractile function and intracellular Ca2+ handling via a NADPH oxidase-dependent mechanism. PLoS One. 2010, 5: e13335-10.1371/journal.pone.0013335.CrossRefPubMedPubMedCentral
15.
Watson LE, Kuo SR, Katki K, Dang T, Park SK, Dostal DE, Tang WJ, Leppla SH, Frankel AE: Anthrax toxins induce shock in rats by depressed cardiac ventricular function. PLoS One. 2007, 2: e466-10.1371/journal.pone.0000466.CrossRefPubMedPubMedCentral
16.
Watson LE, Mock J, Lal H, Lu G, Bourdeau RW, Tang WJ, Leppla SH, Dostal DE, Frankel AE: Lethal and edema toxins of anthrax induce distinct hemodynamic dysfunction. Front Biosci. 2007, 12: 4670-4675. 10.2741/2416.CrossRefPubMed
17.
Moayeri M, Crown D, Dorward DW, Gardner D, Ward JM, Li Y, Cui X, Eichacker P, Leppla SH: The heart is an early target of anthrax lethal toxin in mice: a protective role for neuronal nitric oxide synthase (nNOS). PLoS Pathog. 2009, 5: e1000456-10.1371/journal.ppat.1000456.CrossRefPubMedPubMedCentral
18.
Nishida K, Kyoi S, Yamaguchi O, Sadoshima J, Otsu K: The role of autophagy in the heart. Cell Death Differ. 2009, 16: 31-38. 10.1038/cdd.2008.163.CrossRefPubMed
19.
Ballinger SW: Mitochondrial dysfunction in cardiovascular disease. Free Radic Biol Med. 2005, 38: 1278-1295. 10.1016/j.freeradbiomed.2005.02.014.CrossRefPubMed
20.
Xu L, Fang H, Frucht DM: Anthrax lethal toxin increases superoxide production in murine neutrophils via differential effects on MAPK signaling pathways. J Immunol. 2008, 180: 4139-4147.CrossRefPubMed
21.
Hanna PC, Kruskal BA, Ezekowitz RA, Bloom BR, Collier RJ: Role of macrophage oxidative burst in the action of anthrax lethal toxin. Mol Med. 1994, 1: 7-18.PubMedPubMedCentral
22.
Mearini G, Schlossarek S, Willis MS, Carrier L: The ubiquitin-proteasome system in cardiac dysfunction. Biochim Biophys Acta. 2008, 1782: 749-763. 10.1016/j.bbadis.2008.06.009.CrossRefPubMed
23.
Kang YJ, Chen Y, Epstein PN: Suppression of doxorubicin cardiotoxicity by overexpression of catalase in the heart of transgenic mice. J Biol Chem. 1996, 271: 12610-12616. 10.1074/jbc.271.21.12610.CrossRefPubMed
24.
Park S, Leppla SH: Optimized production and purification of Bacillus anthracis lethal factor. Protein Expr Purif. 2000, 18: 293-302. 10.1006/prep.2000.1208.CrossRefPubMed
25.
Ramirez DM, Leppla SH, Schneerson R, Shiloach J: Production, recovery and immunogenicity of the protective antigen from a recombinant strain of Bacillus anthracis. J Ind Microbiol Biotechnol. 2002, 28: 232-238. 10.1038/sj.jim.7000239.CrossRefPubMed
26.
Ge W, Guo R, Ren J: AMP-dependent kinase and autophagic flux are involved in aldehyde dehydrogenase-2-induced protection against cardiac toxicity of ethanol. Free Radic Biol Med. 2011, 51: 1736-1748. 10.1016/j.freeradbiomed.2011.08.002.CrossRefPubMedPubMedCentral
27.
Turdi S, Fan X, Li J, Zhao J, Huff AF, Du M, Ren J: AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction. Aging Cell. 2010, 9: 592-606. 10.1111/j.1474-9726.2010.00586.x.CrossRefPubMedPubMedCentral
28.
Ma H, Li J, Gao F, Ren J: Aldehyde dehydrogenase 2 ameliorates acute cardiac toxicity of ethanol: role of protein phosphatase and forkhead transcription factor. J Am Coll Cardiol. 2009, 54: 2187-2196. 10.1016/j.jacc.2009.04.100.CrossRefPubMed
29.
Das S, Powell SR, Wang P, Divald A, Nesaretnam K, Tosaki A, Cordis GA, Maulik N, Das DK: Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes. Am J Physiol Heart Circ Physiol. 2005, 289: H361-367. 10.1152/ajpheart.01285.2004.CrossRefPubMed
30.
Edick MJ, Tesfay L, Lamb LE, Knudsen BS, Miranti CK: Inhibition of integrin-mediated crosstalk with epidermal growth factor receptor/Erk or Src signaling pathways in autophagic prostate epithelial cells induces caspase-independent death. Mol Biol Cell. 2007, 18: 2481-2490. 10.1091/mbc.E06-04-0261.CrossRefPubMedPubMedCentral
31.
Skarka L, Ostadal B: Mitochondrial membrane potential in cardiac myocytes. Physiol Res. 2002, 51: 425-434.PubMed
32.
Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000, 19: 5720-5728. 10.1093/emboj/19.21.5720.CrossRefPubMedPubMedCentral
33.
Lawrence WS, Hardcastle JM, Brining DL, Weaver LE, Ponce C, Whorton EB, Peterson JW: The physiologic responses of Dutch belted rabbits infected with inhalational anthrax. Comp Med. 2009, 59: 257-265.PubMedPubMedCentral
34.
Mina B, Dym JP, Kuepper F, Tso R, Arrastia C, Kaplounova I, Faraj H, Kwapniewski A, Krol CM, Grosser M, Glick J, Fochios S, Remolina A, Vasovic L, Moses J, Robin T, DeVita M, Tapper ML: Fatal inhalational anthrax with unknown source of exposure in a 61-year-old woman in New York City. JAMA. 2002, 287: 858-862. 10.1001/jama.287.7.858.CrossRefPubMed
35.
Nemchenko A, Chiong M, Turer A, Lavandero S, Hill JA: Autophagy as a therapeutic target in cardiovascular disease. J Mol Cell Cardiol. 2011, 51: 584-593. 10.1016/j.yjmcc.2011.06.010.CrossRefPubMedPubMedCentral
36.
Zhang Y, Ren J: Autophagy in ALDH2-elicited cardioprotection against ischemic heart disease: slayer or savior?. Autophagy. 2010, 6: 1212-1213. 10.4161/auto.6.8.13652.CrossRefPubMed
37.
Fidzianska A, Bilinska ZT, Walczak E, Witkowski A, Chojnowska L: Autophagy in transition from hypertrophic cardiomyopathy to heart failure. J Electron Microsc (Tokyo). 2010, 59: 181-183. 10.1093/jmicro/dfp048.CrossRef
38.
De Meyer GR, De Keulenaer GW, Martinet W: Role of autophagy in heart failure associated with aging. Heart Fail Rev. 2010, 15: 423-430. 10.1007/s10741-010-9166-6.CrossRefPubMed
39.
Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, Hayakawa Y, Zimmermann R, Bauer E, Klovekorn WP, Schaper J: Myocytes die by multiple mechanisms in failing human hearts. Circ Res. 2003, 92: 715-724. 10.1161/01.RES.0000067471.95890.5C.CrossRefPubMed
40.
Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM: Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res. 2001, 51: 304-312. 10.1016/S0008-6363(01)00290-5.CrossRefPubMed
41.
Shimomura H, Terasaki F, Hayashi T, Kitaura Y, Isomura T, Suma H: Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn Circ J. 2001, 65: 965-968. 10.1253/jcj.65.965.CrossRefPubMed
42.
Huang J, Lam GY, Brumell JH: Autophagy signaling through reactive oxygen species. Antioxid Redox Signal. 2011, 14: 2215-2231. 10.1089/ars.2010.3554.CrossRefPubMed
43.
Andrienko T, Kuznetsov AV, Kaambre T, Usson Y, Orosco A, Appaix F, Tiivel T, Sikk P, Vendelin M, Margreiter R, Saks VA: Metabolic consequences of functional complexes of mitochondria, myofibrils and sarcoplasmic reticulum in muscle cells. J Exp Biol. 2003, 206: 2059-2072. 10.1242/jeb.00242.CrossRefPubMed
44.
Rizzuto R, Brini M, Murgia M, Pozzan T: Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science. 1993, 262: 744-747. 10.1126/science.8235595.CrossRefPubMed
45.
Gustafsson AB, Gottlieb RA: Mechanisms of apoptosis in the heart. J Clin Immunol. 2003, 23: 447-459.CrossRefPubMed
46.
Alileche A, Squires RC, Muehlbauer SM, Lisanti MP, Brojatsch J: Mitochondrial impairment is a critical event in anthrax lethal toxin-induced cytolysis of murine macrophages. Cell Cycle. 2006, 5: 100-106. 10.4161/cc.5.1.2283.CrossRefPubMed
47.
Viola HM, Arthur PG, Hool LC: Transient exposure to hydrogen peroxide causes an increase in mitochondria-derived superoxide as a result of sustained alteration in L-type Ca2+ channel function in the absence of apoptosis in ventricular myocytes. Circ Res. 2007, 100: 1036-1044. 10.1161/01.RES.0000263010.19273.48.CrossRefPubMed
48.
Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J: Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 2007, 100: 914-922. 10.1161/01.RES.0000261924.76669.36.CrossRefPubMed
49.
Ong SB, Gustafsson AB: New roles for mitochondria in cell death in the reperfused myocardium. Cardiovasc Res. 2012, 94: 190-196. 10.1093/cvr/cvr312.CrossRefPubMed
50.
Kostova Z, Tsai YC, Weissman AM: Ubiquitin ligases, critical mediators of endoplasmic reticulum-associated degradation. Semin Cell Dev Biol. 2007, 18: 770-779. 10.1016/j.semcdb.2007.09.002.CrossRefPubMedPubMedCentral
51.
52.
Willis MS, Townley-Tilson WH, Kang EY, Homeister JW, Patterson C: Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circ Res. 2010, 106: 463-478. 10.1161/CIRCRESAHA.109.208801.CrossRefPubMedPubMedCentral
53.
Rubinsztein DC: The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 2006, 443: 780-786. 10.1038/nature05291.CrossRefPubMed
54.
Schlossarek S, Carrier L: The ubiquitin-proteasome system in cardiomyopathies. Curr Opin Cardiol. 2011, 26: 190-195. 10.1097/HCO.0b013e32834598fe.CrossRefPubMed
55.
Willis MS, Patterson C: Into the heart: the emerging role of the ubiquitin-proteasome system. J Mol Cell Cardiol. 2006, 41: 567-579. 10.1016/j.yjmcc.2006.07.015.CrossRefPubMed
56.
Goldberg AL: Protein degradation and protection against misfolded or damaged proteins. Nature. 2003, 426: 895-899. 10.1038/nature02263.CrossRefPubMed
57.
Grune T, Merker K, Sandig G, Davies KJ: Selective degradation of oxidatively modified protein substrates by the proteasome. Biochem Biophys Res Commun. 2003, 305: 709-718. 10.1016/S0006-291X(03)00809-X.CrossRefPubMed
Metadata
Title
Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy
Authors
Machender R Kandadi
Xuejun Yu
Arthur E Frankel
Jun Ren
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2012
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/1741-7015-10-134

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