Abstract
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 on 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).
Highlights
Chagas disease (American trypanosomiasis) is caused by the protozoa parasite Trypanosoma cruzi (T. cruzi), which is transmitted to humans by blood-sucking triatomine bugs and by non-vectorial mechanisms, such as contaminated blood transfusion, organ transplantation, and congenital infection [1, 2]
Chagas disease, caused by the parasite Trypanosoma cruzi, is an endemic disease of LatinAmerican countries, affecting 10 million people are estimated to be infected with T. cruzi, and more than 120 million inhabitants are at risk of infection
Due to immigration towards non-endemic regions, the disease can spread and affect people around the world via blood transfusions. The pathogenesis of this disease is still unwell understood; we previously demonstrated that cardiomyocytes isolated from Chagas patients have an intracellular Ca2+ overload, which appears to be associated with changes in the inositol 1,4,5 trisphosphate (IP3) signaling pathway
Summary
Chagas disease (American trypanosomiasis) is caused by the protozoa parasite Trypanosoma cruzi (T. cruzi), which is transmitted to humans by blood-sucking triatomine bugs and by non-vectorial mechanisms, such as contaminated blood transfusion, organ transplantation, and congenital infection [1, 2]. Chagas disease is a significant public health burden and the leading cause of death and morbidity in Latin American and Caribbean regions [3]. Individuals with Chagas disease have been identified in non-endemic countries in Europe, Canada, and the USA [7, 10], and an estimated 300,000 persons are suffering from this disease who live in the US, especially in Texas and along the Gulf coast [11, 12]. Chagas’ disease has become a potentially severe emerging threat to several countries throughout the world
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