Circulating Plasma miRNA and Clinical/Hemodynamic Characteristics Provide Additional Predictive Information About Acute Pulmonary Thromboembolism, Chronic Thromboembolic Pulmonary Hypertension and Idiopathic Pulmonary Hypertension

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Fabro, Alexandre Todorovic ^{[1, 2]} ; Machado-Rugolo, Juliana ^{[2, 3]} ; Baldavira, Camila Machado ^[2] ; Prieto, Tabatha Gutierrez ^[2] ; Farhat, Cecilia ^[2] ; Rotea ManGone, Flavia Regina ^[4] ; Batah, Sabrina Setembre ^[1] ; Cruvinel, Heloisa Resende ^[1] ; Alda, Maiara Almeida ^[1] ; Monteiro, Jhonatas Sirino ^[5] ; Padua, Adriana Inacio ^[6] ; Morais, Sirlei Siani ^[1] ; Antonio de Oliveira, Rogerio ^[7] ; Santos, Marcel Koenigkam ^[6] ; Baddini-Martinez, Jose Antonio ^[6] ; Setubal, Joao Carlos ^[5] ; Rainho, Claudia Aparecida ^[8] ; Yoo, Hugo Hyung Bok ^[9] ; Silva, Pedro Leme ^{[10, 11]} ; Nagai, Maria Aparecida ^{[4, 12]} ; Capelozzi, Vera Luiza ^[2]

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^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol & Legal Med, Resp Med Lab, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Pathol, Lab Histomorphometry & Lung Genom, Fac Med, Sao Paulo - Brazil

^[3] Sao Paulo State Univ UNESP, Hlth Technol Assessment Ctr NATS, Clin Hosp HCFMB, Sch Med, Botucatu, SP - Brazil

^[4] Canc Inst Sao Paulo ICESP, Ctr Translat Res Oncol, Mol Genet Lab, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Inst Chem, Bioinformat Lab, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Pulm Hypertens Care Ctr, Sao Paulo - Brazil

^[7] Sao Paulo State Univ UNESP, Inst Biosci, Dept Biostat Plant Biol Parasitol & Zool, Botucatu, SP - Brazil

^[8] Sao Paulo State Univ UNESP, Inst Biosci, Dept Chem & Biol Sci, Botucatu, SP - Brazil

^[9] Sao Paulo State Univ UNESP, Botucatu Med Sch, Dept Internal Med, Pulm Hypertens Care Ctr, Sao Paulo - Brazil

^[10] Natl Inst Sci & Technol Regenerat Med, Rio De Janeiro - Brazil

^[11] Univ Fed Rio de Janeiro, Carlos Chagas Filho Biophys Inst, Ctr Ciencias Saude, Lab Pulm Invest, Rio De Janeiro - Brazil

^[12] Sao Paulo State Univ UNESP, Dept Radiol & Oncol, Sch Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN PHARMACOLOGY; v. 12, MAY 28 2021.
• Citações Web of Science: 0

Resumo

Idiopathic pulmonary artery hypertension (IPAH), chronic thromboembolic pulmonary hypertension (CTEPH), and acute pulmonary embolism (APTE) are life-threatening cardiopulmonary diseases without specific surgical or medical treatment. Although APTE, CTEPH and IPAH are different pulmonary vascular diseases in terms of clinical presentation, prevalence, pathophysiology and prognosis, the identification of their circulating microRNA (miRNAs) might help in recognizing differences in their outcome evolution and clinical forms. The aim of this study was to describe the APTE, CTEPH, and IPAH-associated miRNAs and to predict their target genes. The target genes of the key differentially expressed miRNAs were analyzed, and functional enrichment analyses were carried out. The miRNAs were detected using RT-PCR. Finally, we incorporated plasma circulating miRNAs in baseline and clinical characteristics of the patients to detect differences between APTE and CTEPH in time of evolution, and differences between CTEPH and IPAH in diseases form. We found five top circulating plasma miRNAs in common with APTE, CTEPH and IPAH assembled in one conglomerate. Among them, miR-let-7i-5p expression was upregulated in APTE and IPAH, while miRNA-320a was upregulated in CTEP and IPAH. The network construction for target genes showed 11 genes regulated by let-7i-5p and 20 genes regulated by miR-320a, all of them regulators of pulmonary arterial adventitial fibroblasts, pulmonary artery endothelial cell, and pulmonary artery smooth muscle cells. AR (androgen receptor), a target gene of hsa-let-7i-5p and has-miR-320a, was enriched in pathways in cancer, whereas PRKCA (Protein Kinase C Alpha), also a target gene of hsa-let-7i-5p and has-miR-320a, was enriched in KEGG pathways, such as pathways in cancer, glioma, and PI3K-Akt signaling pathway. We inferred that CTEPH might be the consequence of abnormal remodeling in APTE, while unbalance between the hyperproliferative and apoptosis-resistant phenotype of pulmonary arterial adventitial fibroblasts, pulmonary artery endothelial cell and pulmonary artery smooth muscle cells in pulmonary artery confer differences in IPAH and CTEPH diseases form. We concluded that the incorporation of plasma circulating let-7i-5p and miRNA-320a in baseline and clinical characteristics of the patients reinforces differences between APTE and CTEPH in outcome evolution, as well as differences between CTEPH and IPAH in diseases form. (AU)

• Processo FAPESP: 15/06387-0 - Perfil Biomarcador Diagnóstico e Prognóstico dos MicroRNAs Circulantes Plasmáticos na Hipertensão Pulmonar Tromboembólica Crônica
• Beneficiário: Alexandre Todorovic Fabro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/20403-6 - Marcadores biomoleculares de proliferação e remodelamento em doenças respiratórias agudas e crônicas: promissores alvos terapêuticos
• Beneficiário: Vera Luiza Capelozzi
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/06708-0 - Perfil biomarcador diagnóstico e prognóstico dos microRNAs circulantes plasmáticos na hipertensão pulmonar tromboembólica crônica
• Beneficiário: Heloísa Resende Cruvinel
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica