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

by Alfredo Mijares, Raúl Espinosa, José Adams, José R. Lopez

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 to different degrees of cardiac dysfunction. In addition, we have found a significant elevation of diastolic [Na⁺]_d in Chagas’ cardiomyocytes (FCII>FCI) that was greater than control. Exposure of cardiomyocytes to agents that enhance inositol 1,4,5 trisphosphate (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 in Chagas’ cardiomyocytes was related to 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. The effects of ET-1, BK, and IP₃BM on [Ca²⁺]_d were not modified by the removal of extracellular [Ca²⁺]_e. Furthermore, cardiomyocytes from Chagas’ patients had a significant decrease in the sarcoplasmic reticulum (SR) Ca²⁺content compared to control (Control>FCI>FCII), a higher intracellular IP₃ concentration ([IP₃]_i) and markedly depressed contractile properties compared to control cardiomyocytes. These results provide additional and convincing support about the 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 chronic Chagas cardiomyopathy (CC).