• 1

    World Health Organization, 2002. Report on Chagas’ Disease. Geneva: World Health Organization.

  • 2

    Carod-Artal FJ, 2006. Chagas cardiomyopathy and ischemic stroke. Expert Rev Cardiovasc Ther 4 :119–130.

  • 3

    Jelicks LA, Shirani J, Wittner M, Chandra M, Weiss LM, Factor SM, Bekirov I, Braunstein VL, Chan J, Huang H, Tanowitz HB, 1999. Application of cardiac gated magnetic resonance imaging in murine Chagas’ disease. Am J Trop Med Hyg 61 :207–214.

    • Search Google Scholar
    • Export Citation
  • 4

    Huang H, Chan J, Wittner M, Jelicks LA, Morris SA, Factor SM, Weiss LM, Braunstein VL, Bacchi CJ, Yarlett N, Chandra M, Shirani J, Tanowitz HB, 1999. Expression of cardiac cytokines and inducible form of nitric oxide synthase (NOS2) in Trypanosoma cruzi-infected mice. J Mol Cell Cardiol 31 :75–88.

    • Search Google Scholar
    • Export Citation
  • 5

    Jelicks LA, Chandra M, Shirani J, Shtutin V, Tang B, Christ GJ, Factor SM, Wittner M, Huang H, Weiss LM, Mukherjee S, Bouzahzah B, Petkova SB, Teixeira MM, Douglas SA, Loredo ML, D’Orleans-Juste P, Tanowitz HB, 2002. Cardioprotective effects of phosphoramidon on myocardial structure and function in murine Chagas’ disease. Int J Parasitol 32 :1497–1506.

    • Search Google Scholar
    • Export Citation
  • 6

    Chandra M, Shirani J, Shtutin V, Weiss LM, Factor SM, Petkova SB, Rojkind M, Dominguez-Rosales JA, Jelicks LA, Morris SA, Wittner M, Tanowitz HB, 2002. Cardioprotective effects of verapamil on myocardial structure and function in a murine model of chronic Trypanosoma cruzi infection (Brazil Strain): an echocardiographic study. Int J Parasitol 32 :207–215.

    • Search Google Scholar
    • Export Citation
  • 7

    Lima ES, Andrade ZA, Andrade SG, 2001. TNF-alpha is expressed at sites of parasite and tissue destruction in the spleen of mice acutely infected with Trypanosoma cruzi. Int J Exp Pathol 82 :327–336.

    • Search Google Scholar
    • Export Citation
  • 8

    Silva JS, Machado FS, Martins GA, 2003. The role of nitric oxide in the pathogenesis of Chagas disease. Front Biosci 8 :s314–s325.

  • 9

    Funakoshi H, Kubota T, Machida Y, Kawamura N, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A, 2002. Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha. Am J Physiol Heart Circ Physiol 282 :H2159–H2166.

    • Search Google Scholar
    • Export Citation
  • 10

    Goren N, Leiros CP, Sterin-Borda L, Borda E, 1998. Nitric oxide synthase in experimental autoimmune myocarditis dysfunction. J Mol Cell Cardiol 30 :2467–2474.

    • Search Google Scholar
    • Export Citation
  • 11

    Li W, Mital S, Ojaimi C, Csiszar A, Kaley G, Hintze TH, 2004. Premature death and age-related cardiac dysfunction in male eNOS-knockout mice. J Mol Cell Cardiol 37 :671–680.

    • Search Google Scholar
    • Export Citation
  • 12

    Moncada S, Palmer RM, Higgs EA, 1991. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43 :109–142.

  • 13

    Amezcua JL, Palmer RM, de Souza BM, Moncada S, 1989. Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit. Br J Pharmacol 97 :1119–1124.

    • Search Google Scholar
    • Export Citation
  • 14

    Grocott-Mason R, Anning P, Evans H, Lewis MJ, Shah AM, 1994. Modulation of left ventricular relaxation in isolated ejecting heart by endogenous nitric oxide. Am J Physiol 267 :H1804–H1813.

    • Search Google Scholar
    • Export Citation
  • 15

    Klabunde RE, Ritger RC, Helgren MC, 1991. Cardiovascular actions of inhibitors of endothelium-derived relaxing factor (nitric oxide) formation/release in anesthetized dogs. Eur J Pharmacol 199 :51–59.

    • Search Google Scholar
    • Export Citation
  • 16

    Bassenge E, 1991. Endothelium-mediated regulation of coronary tone. Basic Res Cardiol 86 (Suppl 2):69–76.

  • 17

    Balligand JL, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW, 1993. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 91 :2314–2319.

    • Search Google Scholar
    • Export Citation
  • 18

    Gyurko R, Kuhlencordt P, Fishman MC, Huang PL, 2000. Modulation of mouse cardiac function in vivo by eNOS and ANP. Am J Physiol Heart Circ Physiol 278 :H971–H981.

    • Search Google Scholar
    • Export Citation
  • 19

    Suto N, Mikuniya A, Okubo T, Hanada H, Shinozaki N, Okumura K, 1998. Nitric oxide modulates cardiac contractility and oxygen consumption without changing contractile efficiency. Am J Physiol 275 :H41–H49.

    • Search Google Scholar
    • Export Citation
  • 20

    Sumeray MS, Rees DD, Yellon DM, 2000. Infarct size and nitric oxide synthase in murine myocardium. J Mol Cell Cardiol 32 :35–42.

  • 21

    Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC, 1999. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci USA 96 :657–662.

    • Search Google Scholar
    • Export Citation
  • 22

    Haywood GA, Tsao PS, von der Leyen HE, Mann MJ, Keeling PJ, Trindade PT, Lewis NP, Byrne CD, Rickenbacher PR, Bishopric NH, Cooke JP, McKenna WJ, Fowler MB, 1996. Expression of inducible nitric oxide synthase in human heart failure. Circulation 93 :1087–1094.

    • Search Google Scholar
    • Export Citation
  • 23

    Mungrue IN, Husain M, Stewart DJ, 2002. The role of NOS in heart failure: lessons from murine genetic models. Heart Fail Rev 7 :407–422.

    • Search Google Scholar
    • Export Citation
  • 24

    Dawson D, Lygate CA, Zhang MH, Hulbert K, Neubauer S, Casadei B, 2005. nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. Circulation 112 :3729–3737.

    • Search Google Scholar
    • Export Citation
  • 25

    Chandrasekar B, Melby PC, Troyer DA, Freeman GL, 2000. Differential regulation of nitric oxide synthase isoforms in experimental acute chagasic cardiomyopathy. Clin Exp Immunol 121 :112–119.

    • Search Google Scholar
    • Export Citation
  • 26

    Ny L, Li H, Mukherjee S, Persson K, Holmqvist B, Zhao D, Shtutin V, Huang H, Weiss LM, Machado FS, Factor SM, Chan J, Tanowitz HB, Jelicks LA, 2008. A magnetic resonance imaging study of intestinal dilation in Trypanosoma cruzi–infected mice deficient in nitric oxide synthase. Am J Trop Med Hyg 79 :760–767.

    • Search Google Scholar
    • Export Citation
  • 27

    Durand JL, Tang B, Gutstein DE, Petkova S, Teixeira MM, Tanowitz HB, Jelicks LA, 2006. Dyskinesis in Chagasic myocardium: centerline analysis of wall motion using cardiac-gated magnetic resonance images of mice. Magn Reson Imaging 24 :1051–1057.

    • Search Google Scholar
    • Export Citation
  • 28

    De SouzaAP, CohenAW, Park DS, Woodman SE, Tang B, Gutstein DE, Factor SM, Tanowitz HB, Lisanti MP, Jelicks LA, 2005. MR imaging of caveolin gene-specific alterations in right ventricular wall thickness. Magn Reson Imaging 23 :61–68.

    • Search Google Scholar
    • Export Citation
  • 29

    Woodman SE, Park DS, Cohen AW, Cheung MW, Chandra M, Shirani J, Tang B, Jelicks LA, Kitsis RN, Christ GJ, Factor SM, Tanowitz HB, Lisanti MP, 2002. Caveolin-3 knock-out mice develop a progressive cardiomyopathy and show hyperactivation of the p42/44 MAPK cascade. J Biol Chem 277 :38988–38997.

    • Search Google Scholar
    • Export Citation
  • 30

    Chandra M, Tanowitz HB, Petkova SB, Huang H, Weiss LM, Wittner M, Factor SM, Shtutin V, Jelicks LA, Chan J, Shirani J, 2002. Significance of inducible nitric oxide synthase in acute myocarditis caused by Trypanosoma cruzi (Tulahuen strain). Int J Parasitol 32 :897–905.

    • Search Google Scholar
    • Export Citation
  • 31

    Machado FS, Martins GA, Aliberti JC, Mestriner FL, Cunha FQ, Silva JS, 2000. Trypanosoma cruzi-infected cardiomyocytes produce chemokines and cytokines that trigger potent nitric oxide-dependent trypanocidal activity. Circulation 102 :3003–3008.

    • Search Google Scholar
    • Export Citation
  • 32

    Machado FS, Souto JT, Rossi MA, Esper L, Tanowitz HB, Aliberti J, Silva JS, 2008. Nitric oxide synthase-2 modulates chemokine production by Trypanosoma cruzi-infected cardiac myocytes. Microbes Infect 10 :1558–1566.

    • Search Google Scholar
    • Export Citation
  • 33

    Steudel W, Scherrer-Crosbie M, Bloch KD, Weimann J, Huang PL, Jones RC, Picard MH, Zapol WM, 1998. Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3. J Clin Invest 101 :2468–2477.

    • Search Google Scholar
    • Export Citation
  • 34

    Yang XP, Liu YH, Shesely EG, Bulagannawar M, Liu F, Carretero OA, 1999. Endothelial nitric oxide gene knockout mice: cardiac phenotypes and the effect of angiotensin-converting enzyme inhibitor on myocardial ischemia/reperfusion injury. Hypertension 34 :24–30.

    • Search Google Scholar
    • Export Citation
  • 35

    Buys ES, Raher MJ, Blake SL, Neilan TG, Graveline AR, Passeri JJ, Llano M, Perez-Sanz TM, Ichinose F, Janssens S, Zapol WM, Picard MH, Bloch KD, Scherrer-Crosbie M, 2007. Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload. Am J Physiol Heart Circ Physiol 293 :H620–H627.

    • Search Google Scholar
    • Export Citation
  • 36

    Casadei B, 2006. The emerging role of neuronal nitric oxide synthase in the regulation of myocardial function. Exp Physiol 91 :943–955.

  • 37

    Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O’Rourke B, Rodriguez ER, Huang PL, Lima JA, Berkowitz DE, Hare JM, 2002. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 416 :337–339.

    • Search Google Scholar
    • Export Citation
  • 38

    Ziolo MT, Kohr MJ, Wang H, 2008. Nitric oxide signaling and the regulation of myocardial function. J Mol Cell Cardiol 45 :625–632.

  • 39

    Petkova SB, Tanowitz HB, Magazine HI, Factor SM, Chan J, Pestell RG, Bouzahzah B, Douglas SA, Shtutin V, Morris SA, Tsang E, Weiss LM, Christ GJ, Wittner M, Huang H, 2000. Myocardial expression of endothelin-1 in murine Trypanosoma cruzi infection. Cardiovasc Pathol 9 :257–265.

    • Search Google Scholar
    • Export Citation
  • 40

    Ashton AW, Mukherjee S, Nagajyothi FN, Huang H, Braunstein VL, Desruisseaux MS, Factor SM, Lopez L, Berman JW, Wittner M, Scherer PE, Capra V, Coffman TM, Serhan CN, Gotlinger K, Wu KK, Weiss LM, Tanowitz HB, 2007. Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection. J Exp Med 204 :929–940.

    • Search Google Scholar
    • Export Citation
 
 
 

 

 
 
 

 

 

 

 

 

 

Role of NO Synthase in the Development of Trypanosoma cruzi–Induced Cardiomyopathy in Mice

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  • 1 Departments of Physiology and Biophysics, Department of Pathology (Division of Tropical Medicine and Parasitology), and Department of Medicine (Divisions of Infectious Diseases), Albert Einstein College of Medicine, Bronx, New York; Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Instituto Oswaldo Cruz, Rio de Janeiro, Brazil

Trypanosoma cruzi infection results in an increase in myocardial NO and intense inflammation. NO modulates the T. cruzi–induced myocardial inflammatory reaction. NO synthase (NOS)1-, NOS2-, and NOS3-null mice were infected with T. cruzi (Brazil strain). Infected NOS1-null mice had increased parasitemia, mortality, and left ventricular inner diameter (LVID). Chronically infected NOS1- and NOS2-null and wild-type mice (WT) exhibited increased right ventricular internal diameter (RVID), although the fold increase in the NOS2-null mice was smaller. Infected NOS3-null mice exhibited a significant reduction both in LVID and RVID. Reverse transcriptase-polymerase chain reaction showed expression of NOS2 and NOS3 in hearts of infected NOS1-null and WT mice, whereas infected NOS2-null hearts showed little change in expression of other NOS isoforms. Infected NOS3-null hearts showed an increase only in NOS1 expression. These results may indicate different roles for NOS isoforms in T. cruzi–induced cardiomyopathy.

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