Roles of Protein S-Nitrosylation in Endothelial Homeostasis and Dysfunction

Significance: Nitric oxide (NO) plays several distinct roles in endothelial homeostasis. Except for activating the guanylyl cyclase enzyme-dependent cyclic guanosine monophosphate signaling pathway, NO can bind reactive cysteine residues in target proteins, a process known as S-nitrosylation (SNO). SNO is proposed to explain the multiple biological functions of NO in the endothelium. Investigating the targets and mechanism of protein SNO in endothelial cells (ECs) can provide new strategies for treating endothelial dysfunction-related diseases.Recent Advances: In response to different environments, proteomics has identified multiple SNO targets in ECs. Functional studies confirm that SNO regulates NO bioavailability, inflammation, permeability, oxidative stress, mitochondrial function, and insulin sensitivity in ECs. It also influences EC proliferation, migration, apoptosis, and transdifferentiation.Critical Issues: Single-cell transcriptomic analysis of ECs isolated from different mouse tissues showed heterogeneous gene signatures. However, litter research focuses on the heterogeneous properties of SNO proteins in ECs derived from different tissues. Although metabolism reprogramming plays a vital role in endothelial functions, little is known about how protein SNO regulates metabolism reprogramming in ECs.Future Directions: Precisely deciphering the effects of protein SNO in ECs isolated from different tissues under different conditions is necessary to further characterize the relationship between protein SNO and endothelial dysfunction-related diseases. In addition, identifying SNO targets that can influence endothelial metabolic reprogramming and the underlying mechanism can offer new views on the crosstalk between metabolism and post-translational protein modification.