Biomol Ther  
Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model
Janeesh Plakkal Ayyappan1, Kezia lizardo1, Sean Wang2, Edward Yurkow2 and Jyothi F Nagajyothi1,*
1Department of Microbiology, Biochemistry and Molecular Genetics, Public Health Research Institute, New Jersey Medical School, Newark, NJ 07103,
2Rutgers Molecular Imaging Center, Piscataway, NJ 08854, USA
E-mail: jfn31@njms.rutgers.edu
Tel: +1-973-854-3450, Fax: +1-973-854-3101
Received: October 2, 2018; Revised: January 17, 2019; Accepted: January 25, 2019; Published online: March 13, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

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.
Keywords: Chagas disease, Cardiomyopathy, Mitochondrial stress, Endoplasmic reticulum stress, 2-Aminopurine


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