Different signaling pathways are involved in cardiomyocyte survival induced by a Trypanosoma cruzi glycoprotein.
We have recently reported that Trypanosoma cruzi infection protects cardiomyocytes against apoptosis induced by growth factor deprivation. Cruzipain, a major parasite antigen, reproduced this survival effect by a Bcl-2-dependent mechanism. In this study, we have investigated the molecular mechanisms of cruzipain-induced cardiomyocyte protection. Neonatal BALB/c mouse cardiac myocytes were cultured under minimum serum conditions in the presence of cruzipain or T. cruzi (Tulahuen strain). Some cultures were pretreated with the phosphatidylinositol 3-kinase (PI3K) inhibitor Ly294002 or specific inhibitors of the mitogen-activated protein kinase (MAPK) family members such as the mitogen-activated protein kinase kinase (MEK1) inhibitor PD098059, Jun N-terminal kinase (JNK) inhibitor SP600125, p38 MAPK inhibitor SB203580. Inhibition of PI3K and MEK1 but not JNK or p38 MAPK increased the apoptotic rate of cardiomyocytes treated with cruzipain. Phosphorylation of Akt, a major target of PI3K, and ERK1/2, MEK1-targets, was achieved at 15 min and 5 min, respectively. In parallel, these kinases were strongly phosphorylated by T. cruzi infection. In cultures treated with cruzipain, cleavage of caspase 3 was considerably diminished after serum starvation; Bcl-2 overexpression was inhibited by PD098059 but not by Ly294002, whereas Bad phosphorylation and Bcl-xL expression were increased and differentially modulated by both inhibitors. The results suggest that cruzipain exerts its anti-apoptotic property in cardiac myocytes at least by PI3K/Akt and MEK1/ERK1/2 signaling pathways. We further identified a differential modulation of Bcl-2 family members by these two signaling pathways.
Aoki
Maria Del Pilar
Mdel P
CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, CP 5000 Córdoba, Argentina. paoki@bioclin.fcq.unc.edu.ar
Cano
Roxana Carolina
RC
Pellegrini
Andrea Vanina
AV
Tanos
Tamara
T
Guiñazú
Natalia Lorena
NL
Coso
Omar Adrian
OA
Gea
Susana
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000494:pharmacology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D019254:Genes, bcl-2; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000469:parasitology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D015800:Protozoan Proteins; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D014349:Trypanosoma cruzi; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D053148:Caspase 3; D020169:Caspases; D002867:Chromones; D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015800:Protozoan Proteins; D011725:Pyridines; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases; C494820:Bad protein, mouse; C494812:Bcl2l1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C063214:cruzipain; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one