Pathogenic implications of dysregulated miRNAs in propionic acidemia related cardiomyopathy
EntityUAM. Departamento de Biología Molecular
10.1016/j.trsl.2019.12.004Translational Research 218 (2020): 43-56
Funded byThis work was supported by Spanish Ministry of Economy and Competitiveness and European Regional Development Fund (grant number SAF2016-76004-R) and by Fundación Isabel Gemio and Fundación La Caixa (LCF/PR/PR16/ 11110018). AFG is funded by the FPI-UAM program, EAB and ARB by the Spanish Ministry of Science, Innovation and Universities (predoctoral fellowships FPU15/02923 and BES-2014-069420, respectively)
ProjectGobierno de España. SAF2016-76004-R
SubjectsCardiomiRs; GSK3; HCM; mTOR; IVRT; miRNA; PI3K/AKT; ANP; β-MHC; Biología y Biomedicina / Biología
Rights® 2019 Elsevier Inc.
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Cardiac alterations (hypertrophic/dilated cardiomyopathy, and rhythm alterations) are one of the major causes of mortality and morbidity in propionic acidemia (PA), caused by the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC), involved in the catabolism of branched-chain amino acids, cholesterol, and odd-chain fatty acids. Impaired mitochondrial oxidative phosphorylation has been documented in heart biopsies of PA patients, as well as in the hypomorphic Pcca−/−(A138T) mouse model, in the latter correlating with increased oxidative damage and elevated expression of cardiac dysfunction biomarkers atrial and brain natriuretic peptides (ANP and BNP) and beta-myosin heavy chain (β-MHC). Here we characterize the cardiac phenotype in the PA mouse model by histological and echocardiography studies and identify a series of upregulated cardiac-enriched microRNAs (miRNAs) in the PA mouse heart, some of them also altered as circulating miRNAs in PA patients’ plasma samples. In PA mice hearts, we show alterations in signaling pathways regulated by the identified miRNAs, which could be contributing to cardiac remodeling and dysfunction; notably, an activation of the mammalian target of rapamycin (mTOR) pathway and a decrease in autophagy, which are reverted by rapamycin treatment. In vitro studies in HL-1 cardiomyocytes indicate that propionate, the major toxic metabolite accumulating in the disease, triggers the increase in expression levels of miRNAs, BNP, and β-MHC, concomitant with an increase in reactive oxygen species. Our results highlight miRNAs and signaling alterations in the PCC-deficient heart which may contribute to the development of PA-associated cardiomyopathy and provide a basis to identify new targets for therapeutic intervention
Google Scholar:Fulgencio-Covián, Alejandro - Alonso-Barroso, Esmeralda - Guenzel, Adam J. - Rivera-Barahona, Ana - Ugarte, Magdalena - Pérez, Belén - Barry, Michael A. - Pérez-Cerdá, Celia - Richard Rodríguez, Eva María - Ruiz Desviat, Lourdes
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Generation and characterization of a human iPSC line (UAMi004-A) from a patient with propionic acidemia due to defects in the PCCB gene
Generation and characterization of a human iPSC line from a patient with propionic acidemia due to defects in the PCCA gene
Corrigendum to “Generation and characterization of a human iPSC line (UAMi004-A) from a patient with propionic acidemia due to defects in the PCCB gene”