Heme-induced ROS in Trypanosoma cruzi activates CaMKII-like that triggers epimastigote proliferation. One helpful effect of ROS.
Heme is a ubiquitous molecule that has a number of physiological roles. The toxic effects of this molecule have been demonstrated in various models, based on both its pro-oxidant nature and through a detergent mechanism. It is estimated that about 10 mM of heme is released during blood digestion in the blood-sucking bug's midgut. The parasite Trypanosoma cruzi, the agent of Chagas' disease, proliferates in the midgut of the insect vector; however, heme metabolism in trypanosomatids remains to be elucidated. Here we provide a mechanistic explanation for the proliferative effects of heme on trypanosomatids. Heme, but not other porphyrins, induced T. cruzi proliferation, and this phenomenon was accompanied by a marked increase in reactive oxygen species (ROS) formation in epimastigotes when monitored by ROS-sensitive fluorescent probes. Heme-induced ROS production was time- and concentration-dependent. In addition, lipid peroxidation and the formation of 4-hydroxy-2-nonenal (4-HNE) adducts with parasite proteins were increased in epimastigotes in the presence of heme. Conversely, the antioxidants urate and GSH reversed the heme-induced ROS. Urate also decreased parasite proliferation. Among several protein kinase inhibitors tested only specific inhibitors of CaMKII, KN93 and Myr-AIP, were able to abolish heme-induced ROS formation in epimastigotes leading to parasite growth impairment. Taken together, these data provide new insight into T. cruzi- insect vector interactions: heme, a molecule from the blood digestion, triggers epimastigote proliferation through a redox-sensitive signalling mechanism.
Laboratório de Artrópodos Hematófagos, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
Natália Pereira de Almeida
NP
Nogueira
Cintia Fernandes
CF
de Souza
Francis Monique de Souza
FM
Saraiva
Pedro Elias
PE
Sultano
Sergio Ranto
SR
Dalmau
Roberta Eitler
RE
Bruno
Renata de Lima Sales
Rde L
Gonçalves
Gustavo Augusto Travassos
GA
Laranja
Luís Henrique Monteiro
LH
Leal
Marsen Garcia Pinto
MG
Coelho
Claudio A
CA
Masuda
Marcus F
MF
Oliveira
Marcia Cristina
MC
Paes
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006418:Heme / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008018:Life Cycle Stages / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development*
D000975:Antioxidants; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D006418:Heme; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2