Mechanisms of action of sacubitril/valsartan on cardiac remodeling : a systems biology approach
Iborra Egea, Oriol (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Gálvez-Montón, Carolina (Institut Germans Trias i Pujol)
Rudilla, F. (Institut Germans Trias i Pujol)
Perea-Gil, Isaac (Institut Germans Trias i Pujol)
Prat-Vidal, Cristina (Institut Germans Trias i Pujol)
Soler-Botija, Carolina (Institut Germans Trias i Pujol)
Bayés-Genís, Antoni (Institut Germans Trias i Pujol)
Universitat Autònoma de Barcelona

Fecha:	2017
Resumen:	Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling. The new wonder drug in heart failure management, Sacubitril/Valsartan, rejuvenates the heart by preventing its dilation. Using data from myocardial infarction and heart failure samples, we generated a mathematical model to better understand how Sacubitril/Valsartan modulates pathological heart resize and the combined effect of the drug. Our analysis revealed that Sacubitril/Valsartan mainly acts by blocking both, cell death and the pathological makeover of the outer-membrane of the cardiac cells. These two major processes occur after a heart attack. Most importantly, we discovered a core of 8 proteins that emerge as key players in this process. A better understanding of the mechanism of novel cardiovascular drugs at the most basic level may help decipher future therapies and indications.
Ayudas:	Instituto de Salud Carlos III RD16-0011-0006 Instituto de Salud Carlos III CB16-11-00403
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	NPJ Systems Biology and Applications, Vol. 3 (april 2017) , ISSN 2056-7189

DOI: 10.1038/s41540-017-0013-4
PMID: 28649439

9 p, 1.3 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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