The let-7b-5p, miR-326, and miR-125a-3p are associated with left ventricular systolic dysfunction in post-myocardial infarction

Raquel Costa Silva Dantas-Komatsu; Marina Sampaio Cruz; Paula Paccielli Freire; Rosiane Viana Zuza Diniz; Raul Hernandes Bortolin; Otávio Cabral-Marques; Kamilla Batista da Silva Souza; Mario Hiroyuki Hirata; Rosario Dominguez Crespo Hirata; Bruna Zavarize Reis; Igor Jurisica; Vivian Nogueira Silbiger; Andre Ducati Luchessi

doi:10.3389/fcvm.2023.1151855

The let-7b-5p, miR-326, and miR-125a-3p are associated with left ventricular systolic dysfunction in post-myocardial infarction

Front Cardiovasc Med. 2023 May 12:10:1151855. doi: 10.3389/fcvm.2023.1151855. eCollection 2023.

Authors

Raquel Costa Silva Dantas-Komatsu¹, Marina Sampaio Cruz^{1

2}, Paula Paccielli Freire^{1

3}, Rosiane Viana Zuza Diniz⁴, Raul Hernandes Bortolin^{5

6}, Otávio Cabral-Marques^{1

3

5

7

8

9}, Kamilla Batista da Silva Souza³, Mario Hiroyuki Hirata⁵, Rosario Dominguez Crespo Hirata⁵, Bruna Zavarize Reis¹⁰, Igor Jurisica^{11

12

13}, Vivian Nogueira Silbiger^{14

15}, Andre Ducati Luchessi^{1

15}

Affiliations

¹ Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil.
² Division of Cardiology, Department of Medicine, UC San Diego, San Diego, CA, United States.
³ Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
⁴ Department of Clinical Medicine, Center for Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil.
⁵ Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo, Brazil.
⁶ Department of Cardiology, Boston Children's Hospital/Harvard Medical School, Boston, MA, United States.
⁷ Division of Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
⁸ Laboratory of Medical Investigation, University of São Paulo School of Medicine, São Paulo, Brazil.
⁹ Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics, University of Sao Paulo, Sao Paulo, Brazil.
¹⁰ Department of Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil.
¹¹ Division of Orthopedic Surgery, Schroeder Arthritis Institute and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
¹² Departments of Medical Biophysics and Computer Science, and Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
¹³ Slovak Academy of Sciences, Institute of Neuroimmunology, Bratislava, Slovakia.
¹⁴ Department of Clinical and Toxicology Analysis, Federal University of Rio Grande do Norte, Natal, Brazil.
¹⁵ Translational Medicine, The Hospital for Sick Children (SickKids), Toronto, ON, Canada.

Abstract

Background: Acute ST-elevation myocardial infarction (STEMI) can lead to adverse cardiac remodeling, resulting in left ventricular systolic dysfunction (LVSd) and heart failure. Epigenetic regulators, such as microRNAs, may be involved in the physiopathology of LVSd.

Objective: This study explored microRNAs in peripheral blood mononuclear cells (PBMC) of post-myocardial infarction patients with LVSd.

Methods: Post-STEMI patients were grouped as having (LVSd, n = 9) or not LVSd (non-LVSd, n = 16). The expression of 61 microRNAs was analyzed in PBMC by RT-qPCR and the differentially expressed microRNAs were identified. Principal Component Analysis stratified the microRNAs based on the development of dysfunction. Predictive variables of LVSd were investigated through logistic regression analysis. A system biology approach was used to explore the regulatory molecular network of the disease and an enrichment analysis was performed.

Results: The let-7b-5p (AUC: 0.807; 95% CI: 0.63-0.98; p = 0.013), miR-125a-3p (AUC: 0.800; 95% CI: 0.61-0.99; p = 0.036) and miR-326 (AUC: 0.783; 95% CI: 0.54-1.00; p = 0.028) were upregulated in LVSd (p < 0.05) and discriminated LVSd from non-LVSd. Multivariate logistic regression analysis showed let-7b-5p (OR: 16.00; 95% CI: 1.54-166.05; p = 0.020) and miR-326 (OR: 28.00; 95% CI: 2.42-323.70; p = 0.008) as predictors of LVSd. The enrichment analysis revealed association of the targets of these three microRNAs with immunological response, cell-cell adhesion, and cardiac changes.

Conclusion: LVSd alters the expression of let-7b-5p, miR-326, and miR-125a-3p in PBMC from post-STEMI, indicating their potential involvement in the cardiac dysfunction physiopathology and highlighting these miRNAs as possible LVSd biomarkers.

Keywords: PBMC; enrichment analysis; heart failure; left ventricular systolic dysfunction; miRNA; myocardial infarction.

Grants and funding

This study was financed in part by the Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) - Finance Code 001. This work was supported by the São Paulo Research Foundation (FAPESP grant 2020/09146-1 to PPF; 2018/18886-9, 2020/01688-0, and 2020/07069-0 to OCM). IJ was supported in part by funding from Natural Sciences Research Council (NSERC #203475), Canada Foundation for Innovation (CFI #225404, #30865), Ontario Research Fund (RDI #34876), IBM, and Ian Lawson van Toch Fund. The funders had no role in the study's design; the collection, analyses, or interpretation of data; the writing of the manuscript; or the decision to publish the results.