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⁺]_delevation 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.

查加斯心肌病（Chagas cardiomyopathy）是人类查加斯病最严重的临床表现，也是拉丁美洲地区人群发病与死亡的主要诱因。我们此前已证实，从伴不同程度心功能障碍的查加斯病患者体内分离得到的心肌细胞中，存在舒张期钙离子（diastolic Ca²+）稳态异常。当心肌细胞暴露于可提升肌醇1,4,5-三磷酸（inositol 1,4,5-triphosphate, IP3）生成量或浓度的试剂，例如内皮素（endothelin, ET-1）、缓激肽（bradykinin, BK），或是膜通透性肌醇1,4,5-三磷酸六(丁酰氧甲基)酯（IP3BM）时，可引发其舒张期钙离子浓度（[Ca²+]d）升高，且查加斯病患者心肌细胞的该升高幅度始终高于非查加斯病受试者，同时[Ca²+]d的升高幅度与患者心功能障碍的严重程度呈正相关。采用海绵素C（xestospongin-C, Xest-C）——一种膜通透性的IP3受体（IP3 receptors, IP3Rs）选择性阻断剂——对细胞进行孵育，可显著降低查加斯病患者心肌细胞的[Ca²+]d，但对非查加斯病受试者的心肌细胞无显著影响。此外，与健康对照受试者相比，查加斯病患者的心肌细胞具有更高的细胞内IP3浓度（[IP3]i），且收缩功能显著受损。本研究结果为肌醇1,4,5-三磷酸参与不同慢性感染分期患者的查加斯心肌病发病机制提供了进一步的有力佐证，同时也为改善查加斯心肌病患者的心功能与生活质量的新型治疗策略开辟了全新方向。