Unraveling the role of miRNAs as biomarkers in Chagas cardiomyopathy: Insights into molecular pathophysiology

Abstract

Background: Chagas cardiomyopathy (ChCM) is a severe form of Chagas disease and a major cause of cardiovascular morbidity and mortality. The dysregulation of the immune response leads to cardiac remodeling and functional disruptions, resulting in life-threatening complications. Conventional diagnostic methods have limitations, and therapeutic response evaluation is challenging. MicroRNAs (miRNAs), important regulators of gene expression, show potential as biomarkers for diagnosis and prognosis.

Aim: This review aims to summarize experimental findings on miRNA expression in ChCM and explore the potential of these miRNAs as biomarkers of Chagas disease.

Methods: The search was conducted in the US National Library of Medicine MEDLINE/PubMed public database using the terms "Chagas cardiomyopathy" OR "Chagas disease" AND "microRNA" OR "miRNA" OR "miR." Additionally, bioinformatics analysis was performed to investigate miRNA-target interactions and explore enrichment pathways of gene ontology biological processes and molecular functions.

Results: The miR-21, miR-146b, miR-146a, and miR-155 consistently exhibited up-regulation, whereas miR-145 was down-regulated in ChCM. These specific miRNAs have been linked to fibrosis, immune response, and inflammatory processes in heart tissue. Moreover, the findings from various studies indicate that these miRNAs have the potential as biomarkers for the disease and could be targeted in therapeutic strategies for ChCM.

Conclusion: In this review, we point out miR-21, miR-146b, miR-146a, miR-155, and miR-145-5p role in the complex mechanisms of ChCM. These miRNAs have been shown as potential biomarkers for precise diagnosis, reliable prognostic evaluation, and effective treatment strategies in the ChCM.

Fig 1. Flow diagram applied to select studies that involve the function of miRNAs with the development, monitoring, or prognosis of Chagas cardiomyopathy.

Fig 2. miRNAs were included considering the contexts of the studies and type of samples used.

miRNAs were grouped into quadrants according to the context of the studies. The outer edge is color-coded to represent the sample type. The hearts in this figure have been modified from Servier Medical Art [28], licensed under a Creative Common Attribution 3.0 Generic License [29].

Fig 3. Probable main mechanisms involved in the pathophysiology of ChCM.

RTKs: receptor tyrosine kinases; IFNGR1: interferon-gamma receptor 1; MAPK: mitogen-activated protein kinase; AKT: AKT serine/threonine kinase 1; STAT1: signal transducer and activator of transcription 1; NF-κB: nuclear factor kappa B; NOS2: nitric oxide synthase 2; ROS: reactive oxygen species; NO: nitric oxide; ONOO-: peroxynitrite; ΔΨm: mitochondrial membrane potential; mtDNA: mitochondrial DNA; OXPHOS: oxidative phosphorylation; CDND1: cyclin D1; TGFR: transforming growth factor beta receptor; SMAD2/3/5: SMAD family member 2, 3 and 5; SERCA2a: sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; CACNA1C: calcium voltage-gated channel subunit alpha1 C; Ca2+: calcium ion; K+: potassium ion; KCNA1: potassium voltage-gated channel subfamily A member 1; GJA5: gap junction protein alpha 5. The hearts, receptors, ligands, ions channels, Trypanosoma, cell membrane, gap junctions, mitochondria, and lymphocyte cell in this figure have been modified from Servier Medical Art [28], licensed under a Creative Common Attribution 3.0 Generic License [29].

Fig 4. miRNA-target interaction considering biological process and molecular function in the cardiac and immunological context.

The circular network shows miRNA and target interaction. Gene Ontology Biological Process (BM) and Molecular Function (MF) involved with the targets are color-coded at the top of the cycle. (GO: xxx = Gene Ontology entry number).