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1.
Am J Trop Med Hyg ; 79(5): 760-7, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18981519

ABSTRACT

Infection with Trypanosoma cruzi causes megasyndromes of the gastrointestinal (GI) tract. We used magnetic resonance imaging (MRI) to monitor alterations in the GI tract of T. cruzi-infected mice, and to assess the role of nitric oxide (NO) in the development of intestinal dilation. Brazil strain-infected C57BL/6 wild-type (WT) mice exhibited dilatation of the intestines by 30 days post-infection. Average intestine lumen diameter increased by 72%. Levels of intestinal NO synthase (NOS) isoforms, NOS2 and NOS3, were elevated in infected WT mice. Inflammation and ganglionitis were observed in all infected mice. Intestinal dilation was observed in infected WT, NOS1, NOS2, and NOS3 null mice. This study demonstrates that MRI is a useful tool to monitor intestinal dilation in living mice and that these alterations may begin during acute infection. Furthermore, our data strongly suggests that NO may not be the sole contributor to intestinal dysfunction resulting from this infection.


Subject(s)
Chagas Disease/pathology , Intestines/pathology , Magnetic Resonance Imaging/methods , Nitric Oxide Synthase/genetics , Animals , Base Sequence , DNA Primers , Fluorescent Antibody Technique , Intestines/physiopathology , Mice , Nitric Oxide/physiology , Reverse Transcriptase Polymerase Chain Reaction , Trypanosoma cruzi/isolation & purification
2.
Infect Immun ; 73(4): 2496-503, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15784596

ABSTRACT

On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1flox/flox;alpha-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1flox/flox;Tie 2 Cre(+) mice in which the ET-1 gene was deleted from endothelial cells were infected with Trypanosoma cruzi. Genetic controls for these cell-specific ET-1 knockout mice were used. Ninety percentage of all mice survived acute infection with the Brazil strain and were evaluated 130 days postinfection. Inflammation and fibrosis were observed in all infected mice; however, fibrosis was reduced in ET-1flox/flox;alpha-MHC-Cre(+) mice. Cardiac magnetic resonance imaging revealed that infection resulted in a significant increase in right ventricular internal diameter (RVID) in all mice except ET-1flox/flox;alpha-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1flox/flox;alpha-MHC-Cre(+) mice. Echocardiography of the left ventricle demonstrated increased left ventricular end-diastolic diameter, reduced fractional shortening, and decreased relative wall thickness in infected mice. However, the magnitude of the changes was significantly less in ET-1flox/flox;alpha-MHC-Cre(+) mice compared to other groups. These data provide further evidence of a role for ET-1, particularly cardiac myocyte-derived ET-1, in the pathogenesis of chronic Chagasic cardiomyopathy.


Subject(s)
Chagas Cardiomyopathy/etiology , Endothelin-1/physiology , Animals , Chagas Cardiomyopathy/mortality , Chagas Cardiomyopathy/pathology , Chronic Disease , Echocardiography , Endothelin-1/genetics , Magnetic Resonance Imaging , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Parasitemia/mortality , Parasitemia/pathology
3.
Parasitol Res ; 92(6): 496-501, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14999469

ABSTRACT

Chagas' disease, caused by Trypanosoma cruzi, leads to acute myocarditis and chronic cardiomyopathy. Myocardial structure and function were evaluated in T. cruzi (Brazil strain)-infected CD1 mice by histopathology, cardiac gated magnetic resonance imaging (MRI) and transthoracic echocardiography. There was a significant reduction in inflammation and fibrosis in infected mice treated early in infection. In mice treated late in infection, echocardiography revealed a significant increase in the end diastolic diameter and a decrease in percent fractional shortening and relative wall thickness. MRI revealed an increase in the right ventricular internal dimension. These findings, consistent with a dilated cardiomyopathy, were ameliorated in the early but not in the late treatment group, demonstrating that late treatment with verapamil is ineffective in reversing the development of chagasic cardiomyopathy in chronically infected mice. Our data underscore the hypothesis that early events determine the progression to cardiomyopathy and that early treatment with verapamil can prevent such progression.


Subject(s)
Chagas Cardiomyopathy/prevention & control , Chagas Disease/drug therapy , Verapamil/administration & dosage , Animals , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/pharmacology , Cardiomyopathy, Dilated/physiopathology , Chagas Disease/pathology , Chagas Disease/physiopathology , Disease Models, Animal , Echocardiography , Fibrosis , Heart Atria/pathology , Heart Ventricles/diagnostic imaging , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Magnetic Resonance Imaging , Mice , Myocarditis/pathology , Parasitemia , Verapamil/therapeutic use
4.
Am J Physiol Cell Physiol ; 284(2): C457-74, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12388077

ABSTRACT

Recently, development of a caveolin-1-deficient (Cav-1 null) mouse model has allowed the detailed analysis of caveolin-1's function in the context of a whole animal. Interestingly, we now report that the hearts of Cav-1 null mice are markedly abnormal, despite the fact that caveolin-1 is not expressed in cardiac myocytes. However, caveolin-1 is abundantly expressed in the nonmyocytic cells of the heart, i.e., cardiac fibroblasts and endothelia. Quantitative imaging studies of Cav-1 null hearts demonstrate a significantly enlarged right ventricular cavity and a thickened left ventricular wall with decreased systolic function. Histological analysis reveals myocyte hypertrophy with interstitial/perivascular fibrosis. Because caveolin-1 is thought to act as a negative regulator of the p42/44 MAP kinase cascade, we performed Western blot analysis with phospho-specific antibodies that only recognize activated ERK1/2. As predicted, the p42/44 MAP kinase cascade is hyperactivated in Cav-1 null heart tissue (i.e., interstitial fibrotic lesions) and isolated cardiac fibroblasts. In addition, endothelial and inducible nitric oxide synthase levels are dramatically upregulated. Thus loss of caveolin-1 expression drives p42/44 MAP kinase activation and cardiac hypertrophy.


Subject(s)
Cardiomegaly/genetics , Caveolins/deficiency , Extracellular Matrix/genetics , Fibroblasts/enzymology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinases/metabolism , Myocardium/enzymology , Animals , Atrial Natriuretic Factor/genetics , Cardiomegaly/enzymology , Cardiomegaly/pathology , Caveolae/metabolism , Caveolae/pathology , Caveolin 1 , Caveolins/genetics , Cell Membrane/genetics , Cell Membrane/metabolism , Cell Membrane/pathology , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , Female , Fibroblasts/pathology , Hypertrophy, Left Ventricular/genetics , Hypertrophy, Left Ventricular/metabolism , Hypertrophy, Left Ventricular/pathology , Immunohistochemistry , Magnetic Resonance Imaging , Male , Mice , Mice, Knockout , Mitogen-Activated Protein Kinase 3 , Myocardium/pathology , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Ventricular Dysfunction, Right/genetics , Ventricular Dysfunction, Right/metabolism , Ventricular Dysfunction, Right/pathology
5.
Int J Parasitol ; 32(12): 1497-506, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12392915

ABSTRACT

Chagas' disease is an important cause of cardiomyopathy. Endothelin-1, a vasoactive peptide has been implicated in the pathogenesis of chagasic cardiomyopathy. C57BL/6 x 129sv and CD1 mice were thus, infected with trypomastigotes of Trypanosoma cruzi (Brazil strain) and these infected mice were compared with infected mice treated with phosphoramidon. This compound inhibits endothelin-converting enzyme and neutral endopeptidases and does not affect the growth of the parasite in culture. Phosphoramidon was given in a dose of 10mg/kg for the initial 15 days post-infection None of the C57Bl/6 x 129sv mice died as a result of infection. However, there was marked myocardial inflammation and fibrosis in infected, untreated mice. The hearts of the infected, phosphoramidon-treated mice showed significantly less pathology. Cardiac magnetic resonance imaging of infected mice revealed right ventricular dilation that was less severe in those treated with phosphoramidon. Phosphoramidon-treated CD1 mice survived the acute infection. Transthoracic echocardiography demonstrated left ventricular dilation and reduced percent fractional shortening and relative wall thickness. These alterations were also attenuated as a result of phosphoramidon treatment. These data suggest that endothelin-1 contributes to the pathogenesis of chagasic cardiomyopathy and interventions that inhibit the synthesis of endothelin-1 and/or neutral endopeptidase might have a protective effect on myocardial structure and function in murine Chagas' disease.


Subject(s)
Chagas Cardiomyopathy/drug therapy , Chagas Cardiomyopathy/physiopathology , Glycopeptides/pharmacology , Heart/drug effects , Heart/physiopathology , Myocardium/pathology , Protease Inhibitors/pharmacology , Animals , Chagas Cardiomyopathy/parasitology , Chagas Cardiomyopathy/pathology , Disease Models, Animal , Echocardiography , Gene Expression Regulation/drug effects , Glycopeptides/therapeutic use , Heart/parasitology , Magnetic Resonance Imaging , Male , Mice , Mice, Inbred Strains , Myocardium/chemistry , Myocardium/enzymology , Myocardium/metabolism , Protease Inhibitors/therapeutic use , Reverse Transcriptase Polymerase Chain Reaction , Trypanosoma cruzi
6.
Clin Sci (Lond) ; 103 Suppl 48: 263S-266S, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12193100

ABSTRACT

Trypanosoma cruzi is the aetiological agent of Chagas' disease, an important cause of chronic cardiomyopathy. We previously demonstrated a role for endothelin-1 (ET-1) in the pathogenesis of chagasic heart disease. In order to explore further the significance of ET-1 in chagasic heart disease, we infected ET-1 (flox/flox); alpha-MHC-Cre(+) (ET-1KO) mice, in which the ET-1 gene has been deleted from cardiac myocytes, with 10(4) T. cruzi (Brazil strain) trypomastigotes. As controls, we used ET-1 (flox/flox);Cre(-) (FLOX) and C57BL/6x129sv (WT) mice. All mice survived and were evaluated 150-160 days post-infection. Cardiac magnetic resonance imaging revealed a significant increase in right ventricular internal diameter in all infected animals except ET-1KO mice (control WT, 1.6+/-0.10 mm; infected WT, 2.8+/-0.15 mm; control FLOX, 2.04+/-0.02 mm; infected FLOX, 2.76+/-0.28 mm). There was no significant difference in right ventricular internal diameter between infected and uninfected ET-1KO mice (control ET-1KO, 1.83+/-0.11 mm; infected ET-1KO, 2.14+/-0.20 mm). In another series of experiments, transthoracic echocardiography was performed on uninfected as well as infected ET-1KO mice, and uninfected and infected FLOX mice. Both infected groups had an increased left ventricular end-diastolic diameter and reduced fractional shortening. In addition, relative wall thickness was also decreased in infected animals. However, the magnitude of these changes was less in infected ET-1KO mice. These data provide further support for a role for ET-1 in the pathogenesis of chronic chagasic heart disease, and indicate that cardiac myocytes are an important source of ET-1 in this disease.


Subject(s)
Chagas Cardiomyopathy/metabolism , Endothelin-1/metabolism , Myocardium/metabolism , Animals , Chagas Cardiomyopathy/pathology , Chagas Cardiomyopathy/physiopathology , Echocardiography , Endothelin-1/genetics , Magnetic Resonance Imaging , Male , Mice , Mice, Knockout , Myocardium/pathology
7.
Clin Sci (Lond) ; 103 Suppl 48: 267S-271S, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12193101

ABSTRACT

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is an important cause of cardiomyopathy. Microvascular spasm and matrix dissolution, modulated by endothelin-1 (ET-1), is implicated in the pathogenesis of chagasic heart disease. To further elucidate the role of ET-1 in murine chagasic heart disease, C57BL/6 x 129sv mice were infected with T. cruzi (10(3) trypomastigotes of the Brazil strain). These mice are resistant to death during the acute phase but progress to chronic cardiomyopathy. Infected mice were compared with infected mice treated with phosphoramidon, a non-specific metalloprotease inhibitor that is also a potent inhibitor of endothelin-converting enzyme, at a dose of 10 mg/kg. Mice were treated with phosphoramidon for the initial 15 days post infection (PI). All mice were evaluated 200 days PI. Examination of infected, untreated mice revealed marked inflammation, vasculitis and fibrosis. The hearts of infected treated mice had significantly less pathology. Cardiac magnetic resonance imaging (MRI) revealed that right ventricular internal diameter (RVID) was significantly greater (P<0.05) in the infected untreated group (2.9+/-0.22 mm) as compared with the infected treated group (1.73+/-0.35 mm). In another experiment phosphoramidon treatment was also tested in CD1 mice, which have a high mortality during the acute phase of infection with 5 x 10(4) trypomastigotes of the Brazil strain. One group of CD1 mice was untreated while the other group received phosphoramidon for the initial 15 days PI. The mortality rate in untreated mice was 70% by day 35 PI, while all treated infected mice lived. The parasitemia in both groups was similar. The cardiac pathology was more severe in untreated mice. MRI revealed the RVID to be significantly greater in the untreated infected group as compared with the phosphoramidon-treated infected mice (2.74+/-0.03 mm versus 1.64+/-0.4 mm P<0.05). Transthoracic echocardiography revealed that the percentage fractional shortening was reduced in infected CD1 mice but not in those infected mice treated with phosphoramidon. There was no effect of phosphoramidon in uninfected mice. Phosphoramidon (100 microg/ml) had no effect on parasites in vitro. These data are consistent with the hypothesis that ET-1 contributes to the pathogenesis of murine chagasic cardiomyopathy and suggests that interventions targeting ET-1 would improve the outcome in chagasic heart disease.


Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Chagas Cardiomyopathy/drug therapy , Glycopeptides/therapeutic use , Animals , Chagas Cardiomyopathy/pathology , Chagas Cardiomyopathy/physiopathology , Echocardiography , Endothelin-Converting Enzymes , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Glycopeptides/pharmacology , Magnetic Resonance Imaging , Male , Metalloendopeptidases , Mice , Mice, Inbred C57BL , Myocardium/pathology , Trypanosoma cruzi/drug effects
8.
Int J Parasitol ; 32(7): 897-905, 2002 Jun 15.
Article in English | MEDLINE | ID: mdl-12062561

ABSTRACT

Chagas' disease, caused by Trypanosoma cruzi, is associated with myocarditis and expression of myocardial cytokines and inducible nitric oxide synthase (NOS2). To assess the functional significance of NOS2 in murine Chagas' disease, we infected NOS2 knockout (NOS2(-/-)) and C57BL/6x129sv (wild type) mice with the Tulahuen strain of T. cruzi. Serial transthoracic echocardiography was performed to assess the progression of left and right ventricular dysfunction in infected mice. Uninfected wild type and NOS2(-/-) mice served as controls. At day 10 post-infection (p.i.), infected wild type mice had larger left ventricular end-diastolic diameter (2.52+/-0.14-vs-2.11+/-0.06 mm, P<0.02) and right ventricle (0.6+/-0.2-vs-0 visual grade, P<0.02) as compared with uninfected wild type mice. At day 19 p.i., compared with uninfected controls, infected wild type mice had larger left ventricular end-diastolic diameter (3.30+/-0.29-vs-2.11+/-0.07 mm), left ventricular end-systolic diameter (1.86+/-0.29-vs-0.88+/-0.05 mm), right ventricle (1.6+/-0.2-vs-0 visual grade), lower heart rate (413+/-27-vs-557+/-25 beats per min), left ventricular relative wall thickness (0.44+/-0.05-vs-0.64+/-0.03) and fractional shortening (45+/-4-vs-57+/-2%) [P<0.05 for all]. In contrast, no differences in left ventricular end-diastolic diameter or fractional shortening were noted among infected and uninfected NOS2(-/-) mice at day 19 p.i. Compared with uninfected controls, infected NOS2(-/-) mice had significantly lower heart rate (272+/-23-vs-512+/-31 beats per min, P<0.01) and larger right ventricle (0.6+/-0.2-vs-0, P<0.05 visual grade). The magnitude of right ventricular dilation in NOS2(-/-) mice was less than that observed in infected wild type mice. At necropsy, the heart weight was greater (129+/-16-vs-109+/-7 mg, P=0.02) and myocardial inflammation more severe in infected wild type compared with infected NOS2(-/-) mice. Myocardial interleukin (IL)-1beta, IL-6, tumour necrosis factor-alpha, and interferon-gamma were induced in all infected mice. These data indicate that nitric oxide derived from NOS2 plays an important role in the development and progression of ventricular dilation and systolic dysfunction in acute murine chagasic myocarditis caused by infection with the Tulahuen strain.


Subject(s)
Chagas Disease/enzymology , Myocarditis/enzymology , Nitric Oxide Synthase/metabolism , Trypanosoma cruzi/enzymology , Animals , Chagas Disease/parasitology , Chagas Disease/pathology , Cytokines/analysis , Cytokines/biosynthesis , Electrocardiography , Gene Expression Regulation/genetics , Histocytochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocarditis/parasitology , Myocarditis/pathology , Nitric Oxide Synthase Type II , Parasitemia , RNA, Protozoan/chemistry , RNA, Protozoan/genetics , Reverse Transcriptase Polymerase Chain Reaction , Trypanosoma cruzi/genetics , Trypanosoma cruzi/metabolism
9.
Int J Parasitol ; 32(2): 207-15, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11812498

ABSTRACT

Verapamil has been shown to attenuate the extent of myocardial injury in murine models of chronic Trypanosoma cruzi infection. Infected mice treated with verapamil have significantly lower myocardial expression of inducible nitric oxide synthase and cytokines and substantially less inflammatory infiltrate and myocyte necrosis at necropsy. In the present study, we examined the cardiac structural and functional correlates of verapamil treatment in CD1 mice infected with the Brazil strain of T. cruzi using serial transthoracic echocardiography. There were four groups: uninfected- untreated control, uninfected-verapamil-treated, infected-untreated control, and infected-verapamil-treated. Verapamil was given in drinking water (1 gm/l) continuously from the day of infection for a total of 120 days. Mice were evaluated at baseline, 40 and 150 days p.i. Mice in the untreated-infected group compared with the mice in the infected-verapamil-treated group showed thinning of the left ventricular wall (0.84 +/- 0.02-vs-0.92 +/- 0.04, P<0.05 mm), increase in the left ventricular end-diastolic diameter (3.27 +/- 0.15-vs-2.74 +/- 0.05 mm, P<0.05) and reduction in percent fractional shortening (37 +/- 2-vs-53 +/- 4%, P<0.05). No differences in these parameters were noted among mice in the uninfected-untreated and uninfected-verapamil-treated groups. Furthermore, right ventricular dilation was more severe in mice from the infected-untreated group as compared with those in the infected- verapamil-treated group (visual grade 1.9 +/- 0.4-vs-1.0 +/- 0.2, P<0.05). At necropsy, the extent of myocardial injury, as determined histologically, was significantly greater in the infected-untreated mice. These data provide cardiac structural and functional correlates for the previously observed cardioprotective effects of verapamil in chronic chagasic cardiomyopathy.


Subject(s)
Calcium Channel Blockers/pharmacology , Cardiotonic Agents/pharmacology , Chagas Disease/drug therapy , Myocardium/pathology , Trypanosoma cruzi/metabolism , Ventricular Function/drug effects , Verapamil/pharmacology , Animals , Calcium Channel Blockers/therapeutic use , Cardiotonic Agents/therapeutic use , Chagas Disease/diagnostic imaging , Chagas Disease/pathology , Chagas Disease/physiopathology , Collagen/analysis , Collagen/biosynthesis , Disease Models, Animal , Echocardiography , Histocytochemistry , Male , Mice , Trypanosoma cruzi/drug effects , Verapamil/therapeutic use
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