Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-Nitroso- N -Pivaloyl- d -Penicillamine: Implications for Improved Diastolic Function and Cardiac Performance.

Abstract: We previously reported a novel compound called S-nitroso- N -pivaloyl- d -penicillamine (SNPiP), which was screened from a group of nitric oxide donor compounds with a basic chemical structure of S-nitroso- N -acetylpenicillamine, to activate the nonneuronal acetylcholine system. SNPiP-treated mice exhibited improved cardiac output and enhanced diastolic function, without an increase in heart rate. The nonneuronal acetylcholine-activating effects included increased resilience to ischemia, modulation of energy metabolism preference, and activation of angiogenesis. Here, we performed transcriptome analysis of SNPiP-treated mice ventricles to elucidate how SNPiP exerts beneficial effects on cardiac function. A time-course study (24 and 48 hours after SNPiP administration) revealed that SNPiP initially induced Wnt and cyclic guanosine monophosphate-protein kinase G signaling pathways, along with upregulation of genes involved in cardiac muscle tissue development and oxytocin signaling pathway. We also observed enrichment of glycolysis-related genes in response to SNPiP treatment, resulting in a metabolic shift from oxidative phosphorylation to glycolysis, which was suggested by reduced cardiac glucose contents while maintaining adenosine tri-phosphate levels. In addition, SNPiP significantly upregulated atrial natriuretic peptide and sarcolipin, which play crucial roles in calcium handling and cardiac performance. These findings suggest that SNPiP may have therapeutic potential based on the pleiotropic mechanisms elucidated in this study.