Circulating miRNAs as Potential Biomarkers Associated with Cardiac Remodeling and Fibrosis in Chagas Disease Cardiomyopathy

Abstract

Chagas disease (CD) affects approximately 6–7 million people worldwide, from which 30% develop chronic Chagas cardiomyopathy (CCC), usually after being asymptomatic for years. Currently available diagnostic methods are capable of adequately identifying infected patients, but do not provide information regarding the individual risk of developing the most severe form of the disease. The identification of biomarkers that predict the progression from asymptomatic or indeterminate form to CCC, may guide early implementation of pharmacological therapy. Here, six circulating microRNAs (miR-19a-3p, miR-21-5p, miR-29b-3p, miR-30a-5p, miR-199b-5p and miR-208a-3p) were evaluated and compared among patients with CCC (n = 28), CD indeterminate form (n = 10) and healthy controls (n = 10). MiR-19a-3p, miR-21-5p, and miR-29b-3p were differentially expressed in CCC patients when compared to indeterminate form, showing a positive correlation with cardiac dysfunction, functional class, and fibrosis, and a negative correlation with ejection fraction and left ventricular strain. Cardiac tissue analysis confirmed increased expression of microRNAs in CCC patients. In vitro studies using human cells indicated the involvement of these microRNAs in the processes of cardiac hypertrophy and fibrosis. Our study suggests that miRNAs are involved in the process of cardiac fibrosis and remodeling presented in CD and indicate a group of miRNAs as potential biomarkers of disease progression in CCC.

MicroRNAs: Biological Regulators in Pathogen–Host Interactions

“…Higher levels of miR-208a in the plasma samples from human chronic Chagas disease were described to be correlated with TGF-β-stimulation and the regulation of genes involved in cardiac hypertrophy and fibrosis [118][119][120]. Nonaka and coworkers also found increased levels of miR-19a-3p, miR-29b-3p, and miR-30a-5p in plasma and miR-19a-3p, miR-21-5p, miR-29b-3p, miR-30a-5p, miR-199b-5p, and miR-208a-3p in heart samples from chronic Chagas patients, which was correlated with miR-21 upregulation in TGF-β-stimulated fibroblasts [121]. These miRNAs can regulate distinct genes and mechanisms, such as miR-193b targeting of TGF-β2 [122], apoptosis by miR-338 targeting of apoptosis-associated tyrosine kinase (AATK), and can also be induced by pro-inflammatory cytokines, such as those observed for TNF-α and IL-6 stimulation, that upregulate miR-199a in human adipocytes [123].…”

NormiRazor: tool applying GPU-accelerated computing for determination of internal references in microRNA transcription studies

“…One of such fields, that prompted our group to review available normalization algorithms, is research on circulating microRNAs (miRNAs) as potential biomarkers [5,6]. In past years, circulating miRNAs were shown as very promising diagnostic tools in cancer research [7,8], radiation exposure [9], diabetes [10], cardiology [11] and numerous other areas. Problems with finding optimal normalization strategy often pose a major obstacle in translating results of research into clinically applicable diagnostic tools [12,13].…”

Human microRNAs in host–parasite interaction: a review

“…2c) chronic CD and they suggested that this might be correlated with TGF-β stimulation and regulation of genes involved in cardiac hypertrophy and fibrosis, such as GATA binding 4 (GATA4) and Gap Junction Alpha-5 (GJA5). More recently, Nonaka et al (2019) reported an elevated level of miR-19a-3p, miR-29b-3p, and miR-30a-5p in serum, and miR-19a-3p, miR-21-5p, miR-29b-3p, miR-30a-5p, and miR-199b-5p in heart samples from chronic CD patients suggesting that some of them might be correlated with cardiac injury and disease severity, targeting Natriuretic Peptide B (NPPB) and Collagen type I Alpha 1 chain (COL1A1). However, the relationship of miRNAs with CD pathogenesis could be further explored in order to validate new biomarkers or molecular targets for therapeutic intervention.…”