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Published on: September 18, 2017
[Dysfunction of diastolic [Ca²⁺] in cardiomyocytes isolated from chagasic patients]
José R López1, Raúl Espinosa, Patricia Landazuru
1Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
Insights
Chagas disease disrupts intracellular calcium regulation in heart cells, worsening with cardiac dysfunction. This calcium imbalance is linked to altered inositol 1,4,5-trisphosphate signaling.
Area of Science:
- Cardiology
- Cell Physiology
- Parasitology
Background:
- Chagas disease, endemic in Latin America, is caused by Trypanosoma cruzi.
- Cardiac dysfunction is a common manifestation of Chagas disease.
- Intracellular calcium regulation is critical for cardiomyocyte function.
Purpose of the Study:
- To investigate intracellular calcium regulation in cardiomyocytes from Chagasic patients.
- To correlate calcium handling abnormalities with the degree of cardiac dysfunction.
Main Methods:
- Isolated cardiomyocytes from Chagasic patients and controls.
- Measurement of diastolic calcium concentration ([Ca²⁺](d)) and resting membrane potential using microelectrodes.
- Pharmacological interventions with a phospholipase C antagonist (U-73122) and an inositol 1,4,5-trisphosphate receptor blocker (2-APB).
Main Results:
- Significant elevation of [Ca²⁺](d) in Chagasic cardiomyocytes, increasing with disease severity (123% to 738%).
- Partial depolarization of membrane potential observed in Chagasic patients.
- U-73122 and 2-APB partially reverted [Ca²⁺](d) alterations; phenylephrine-induced calcium increase was exacerbated in Chagasic cells and blocked by 2-APB.
Conclusions:
- Cardiomyocytes from Chagasic patients exhibit impaired diastolic calcium regulation.
- This calcium dysregulation correlates with cardiac abnormalities and disease stage.
- The disturbance is linked to altered intracellular signaling via inositol 1,4,5-trisphosphate.
Introduction And Objectives:
Chagas is an endemic disease in Latin America, caused by the parasite Trypanosoma cruzi, which usually affects the functioning of the heart. We have studied the regulation of intracellular calcium in cardiomyocytes isolated from chagasic patients with different degrees of heart dysfunction.
Methods:
Calcium selective microelectrodes were used to simultaneously measure diastolic calcium concentration ([Ca²⁺](d)) and resting membrane potential in endomyocardial biopsies obtained from chagasic patients and controls.
Results:
The [Ca²⁺](d) increased by 123%, 295%, and 738% in chagasic patients in functional class I, II, and III, respectively, in relation to controls. Membrane potential showed a partial depolarization of 6% in functional class I, 10% in functional class II, and 22% in functional class III, compared to control values. Alteration in the [Ca²⁺](d) was partially reverted by 1-[6-[[(17ß)-3-metoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122), a β-phospholipase C antagonist, and by 2-aminoethoxydiphenyl-borate (2-APB), an inositol 1,4,5-trisphosphate receptor blocker. Phenylephrine, an agent that induces a rapid transient increase in 1,4,5-trisphosphate intracellular content, produced a rise in [Ca²⁺](d), higher in chagasic cardiomyocytes than in controls, and its effect was fully inhibited by 2-APB.
Conclusions:
In cardiomyocytes from chagasic patients there is a dysfunction of the regulation of the [Ca²⁺](d), which correlates with the cardiac abnormalities observed in the different stages of the disease. This disturbance in the regulation of intracellular calcium appears to be associated with alterations in the regulation of intracellular messenger inositol 1,4,5-trisphosphate.
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