Biomol Ther.  2019 Jul;27(4):386-394. 10.4062/biomolther.2018.193.

Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model

• Ayyappan J
• lizardo K
• Wang S
• Yurkow E
• Nagajyothi JF

• KMID: 2455094
• DOI: http://doi.org/10.4062/biomolther.2018.193

Abstract

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor (P-elF2α) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.

Keyword

Chagas disease; Cardiomyopathy; Mitochondrial stress; Endoplasmic reticulum stress; 2-Aminopurine

MeSH Terms

2-Aminopurine*
Animals
Cardiomyopathies*
Chagas Disease*
Endoplasmic Reticulum
Endoplasmic Reticulum Stress
Heart
Humans
Lipid Droplets
Lipid Metabolism
Mice
Mortality
Pathology
Peptide Initiation Factors
Trypanosoma cruzi
Ultrasonography
2-Aminopurine
Peptide Initiation Factors