Abstract
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.
Highlights
Heart failure (HF) is characterized at the myocardial level by ventricular remodeling and dysfunction,[1, 2] and clinically, by pump failure and sudden death
Sacubitril acts by preventing the breakdown of endogenous vasoactive peptides, including natriuretic peptides (ANP, BNP, and CNP), thereby limiting myocardial cell death
The molecular mechanisms of Sacubitril and Valsartan alone are not associated with left ventricular extracellular matrix remodeling (LVEMR), and it is only their combination that activates these molecular processes
Summary
Heart failure (HF) is characterized at the myocardial level by ventricular remodeling and dysfunction,[1, 2] and clinically, by pump failure and sudden death. While the mechanism of action for this combination drug is likely to involve the regulation of adverse tissue remodeling, the molecular mechanisms underlying the beneficial effects of Sacubitril/Valsartan (a salt complex at a 1:1 molar ratio),[8, 9] are, at present, incompletely characterized. A myocardial transcriptome obtained in response to MI in swine was analyzed to address post-infarction ventricular remodeling.[14] HF remodeling was studied using public data available in gene expression omnibus (GEO).[15] A dedicated database and a series of mathematical models, adjusted to known physiological processes, were used to predict the precise molecular effects of Sacubitril/Valsartan upon the myocardium and vasculature
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