Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
Departamento de Cardiología, Hospital Miguel Pérez Carreño, Instituto venezolano de los Seguros Sociales, Caracas, Venezuela.
PLoS Negl Trop Dis. 2020 Apr 10;14(4):e0008162. doi: 10.1371/journal.pntd.0008162. eCollection 2020 Apr.
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).
克氏锥虫心肌病是人类克氏锥虫病最严重的表现形式，也是拉丁美洲发病率和死亡率的主要原因。我们之前证明，在不同程度心功能障碍的克氏锥虫病患者分离的心肌细胞中存在舒张期 Ca2+改变。此外，我们发现克氏锥虫病心肌细胞（FCII>FCI）中舒张期[Na+]d显著升高，且高于对照组。用能够增强肌醇 1,4,5 三磷酸（IP3）生成或浓度的物质（如内皮素（ET-1）或缓激肽（BK））或膜通透的肌醇 1,4,5-三磷酸六（丁酸酯基）酯（IP3BM）处理心肌细胞，会导致舒张期 Ca2+浓度（[Ca2+]d）升高，而克氏锥虫病心肌细胞的[Ca2+]d 升高幅度总是大于非克氏锥虫病患者，并且克氏锥虫病心肌细胞[Ca2+]d 的升高幅度与心功能障碍的程度相关。用膜通透的 IP3 受体（IP3R）选择性阻断剂 Xestospongin-C（Xest-C）孵育，可显著降低克氏锥虫病心肌细胞的[Ca2+]d，但对非克氏锥虫病细胞没有显著影响。ET-1、BK 和 IP3BM 对[Ca2+]d 的影响不会因去除细胞外 Ca2+（[Ca2+]e）而改变。此外，与对照组（Control>FCI>FCII）相比，克氏锥虫病患者的心肌细胞肌浆网（SR）Ca2+含量明显降低，细胞内 IP3 浓度[IP3]i较高，与对照组心肌细胞相比，收缩性能明显降低。这些结果为 IP3 在不同慢性感染阶段的克氏锥虫病患者的发病机制中的作用提供了额外的、令人信服的支持。此外，这些发现为改善慢性克氏锥虫病患者的心脏功能和生活质量的新型治疗策略开辟了道路。
