Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas’ human cardiomyocytes

Chagas cardiomyopathy is the most severe
manifestation of human Chagas disease and represents the major cause of
morbidity and mortality in Latin America. We previously demonstrated diastolic
Ca2+ alterations in cardiomyocytes isolated from Chagas’ patients
with different degrees of cardiac dysfunction. Exposure of cardiomyocytes to agents that enhance inositol
1,4,5 triphosphate (IP3)
generation or concentration like endothelin (ET-1) or bradykinin
(BK), or membrane-permeant
myoinositol 1,4,5-trisphosphate hexakis(butyryloxy-methyl) esters (IP3BM) caused
an elevation in diastolic [Ca2+] ([Ca2+]d)
that was always greater in cardiomyocytes from Chagas’ than non- Chagas’ subjects, and the magnitude of the [Ca2+]d
elevation was related with the degree of cardiac dysfunction. Incubation
with xestospongin-C (Xest-C) a membrane-permeable selective blocker of the
IP3 receptors (IP3Rs) significantly
reduced [Ca2+]d in Chagas’ cardiomyocytes
but did not have a significant effect in non- Chagas’ cells. Furthermore, cardiomyocytes
from Chagas’ patients had a higher intracellular IP3 concentration ([IP3]i)
and markedly depressed contractile properties compared to control subjects. These results provide additional and
convincing support about implications of IP3 in the pathogenesis of Chagas
cardiomyopathy in patients at different stages of chronic infection. Additionally,
these findings open the door for novel therapeutic strategies oriented to
improve cardiac function and quality of life of individuals suffering from
Chagas cardiomyopathy.