Effects of the Controlled Underexpression of IGFBP7 through the Drug Sacubitril/Valsartan for Geriatric Diseases

Geriatric diseases account for approximately 75% of all deaths since the 20th century. Despite their apparent diversity, these conditions may share common upstream mechanisms. This study investigates the upstream mechanisms of cellular aging and their connections to geriatric diseases through the analysis of Sacubitril/Valsartan, a novel drug for Heart Failure with preserved Ejection Fraction (HFpEF), on Insulin Growth Factor Binding Protein 7 (IGFBP7). Preliminary computational modeling using AutoDock Vina displayed binding affinities of −6.2 and −5.4 kcal/mol for Sacubitril and Valsartan, respectively, with IGFBP7, surpassing the average binding affinity of −4.6 kcal/mol for five control drugs. Protein-ligand interaction profiling identified eight hydrophobic interactions, two hydrogen bonds, and one salt bridge in the complex. Further binding site analysis determined the most probable binding site near amino acid 155 in the IGFBP7 sequence. To further elucidate the role of IGFBP7, a Bayesian probabilistic network analyzed heart failure datasets from the GEO database, indicating significant IGFBP7 upregulation in 89% of heart failure patients, with 97% of the fourth quartile exhibiting heart failure. A similar machine learning analysis of cerebral endothelial datasets in post-MCAO mice revealed that > 87.4% of stroke cases belonged to the highest quartile of IGFBP7 expression, with an over threefold increase compared to the controls. Complementing computational and statistical findings, in-vitro experiments were conducted using primary brain microvascular endothelial cells (C57BL/6 with Sacubitril/Valsartan at 0, 20, 40, and 60 µM under normoxic and hypoxic conditions. Cell viability assays determined an IC50 of ~55 µM, with hypoxic conditions reducing viability. These results suggest Sacubitril/Valsartan’s potential to modulate apoptosis and influence vascular aging. These findings identify IGFBP7 as a potential upstream factor in geriatric diseases and highlight its therapeutic potential as a target for vascular drugs like Sacubitril/Valsartan.