HIF-1a/purinergic axis is altered in patients with chronic Chagas disease

EBERHARDT NATALIA; SANMARCO LILIANA; BERGERO GASTÓN; VISCONTI LAURA; MINGUEZ ANGEL RAMÓN; VIGLIANO CARLOS; AOKI PILAR

Congreso; Congreso anual SAI SAIC SAFIS 2018; 2018

Introduction: The molecular mechanisms involved in the development of human chronic Chagas cardiomyopathy (CCC) are still largely unknown. Purinergic system components have taken a robust significance as danger signals and modulators of immunity. Ischemic cells release ATP (inflammasome activator), which is metabolized by CD39/CD73 ectoenzymes to anti-inflammatory adenosine. We have reported that CD73 pharmacological inhibition during acute T. cruzi murine infection reduced progression of CCC. The aim of this study was to explore the hypoxia-inducible factor-1α (HIF-1α)/purinergic system axis in immune cells from infected individuals and in cardiac explants from CCC patients. Materials and Methods: Seropositive patients (n = 24) were evaluated clinically and by electrocardiogram and chest X-ray. The uninfected control group (n = 24) consisted of age-matched individuals. Cardiac tissue samples from end-stage CCC patients were stained by IHC/IF. The myocarditis degree was determined considering the number of CD68+ plus CD3+ cells, as follow: Severe≥ median number; Moderate 25-50th percentile; or Mild≤ 25th percentile. Results: In comparison with control donors, infected patients showed higher frequency of HIF-1α+ and IL-1β+ circulating monocytes with increased nitric oxide production (p<0.05). Moreover, while lymphocytes exhibited decreased expression of HIF-1α-target molecules, CD39 and CD73 (p<0.05), concomitant with higher ATP serum levels (p<0.05); the percentage of CD39+ monocytes augmented (p<0.05). Heart samples with severe myocarditis showed a prevalence of CD3+ cells over other infiltrating mononuclear cells (p<0.001) and the number of T cells positively correlated with HIF-1α expression (p<0.05). In addition, severe CCC hearts showed higher HIF-1α expression compared to moderate or mild disease (p<0.05). Furthermore, a marked CD73 expression was observed in infiltrating and endothelial cells. Conclusion: Summing up, infected patients exhibited an inflammatory state potentiated by altered purinergic pathways that may be involved in cardiac dysfunction. These findings suggest that targeting the hypoxic/adenosine axis could be used therapeutically for Chagas disease patients.