Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach

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.

The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction

“…This resulted in less dilation of LVESV, a more preserved LVEF and a reduction in the A‐wave velocity . Mechanistically, sacubitril is implicated in attenuating cardiomyocyte cell death, hypertrophy and impaired myocyte contractility . Based on these preclinical and mechanistic evaluations of sacubitril, the incremental beneficial effect on systolic and diastolic function might seem more straightforward.…”

Muscle molecular adaptations to endurance exercise training are conditioned by glycogen availability: a proteomics‐based analysis in the McArdle mouse model

“…; Iborra‐Egea et al . ). This approach involves the generation of mathematical models of the biological processes through the use of artificial intelligence techniques.…”

“…); pathological conditions, signatures and pathways from the Biological Effectors Database (BED; Iborra‐Egea et al . ) and the regulatory molecular mechanisms included in Transcriptional Regulatory Relationships Unraveled by Sentence‐based Text‐mining (TRRUST) database (Han et al . ).…”

Three-Dimensional and Biomimetic Technology in Cardiac Injury After Myocardial Infarction: Effect of Acellular Devices on Ventricular Function and Cardiac Remodelling

“…These membranes illed with a self-assembling peptide hydrogel and cell with cardiac potential were fully vascularized with functional vessel and observed via echocardiography positive efects on global cardiac motility [42]. The results suggested, in this case, that the beneits of biodegradable scafolds were not only due to local reduction in scar size, but to a more general event [43,44]. Recent experimental studies have failed to answer important aspects of cell therapy.…”