We previously reported a novel compound called S-nitroso-N-pivaloyl-D-penicillamine (SNPiP), which was screened from a group of nitric oxide (NO) donor compounds with a basic chemical structure of S-nitroso-N-acetylpenicillamine (SNAP), to activate the non-neuronal acetylcholine (NNA) system. SNPiP-treated mice exhibited improved cardiac output and enhanced diastolic function, without an increase in heart rate. The NNA-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 h after SNPiP administration) revealed that SNPiP initially induced Wnt and cGMP-protein kinase G (PKG) 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 ATP levels. Additionally, SNPiP significantly upregulated atrial natriuretic peptide (ANP) and sarcolipin (SLN), 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.

中文翻译：

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转录组分析揭示 S-亚硝基-N-新戊酰-D-青霉胺 (SNPiP) 增强心脏发生相关信号通路：对改善舒张功能和心脏性能的影响。

我们之前报道了一种名为S-亚硝基-N-新戊酰-D-青霉胺（SNPiP）的新型化合物，它是从一组一氧化氮（NO）供体化合物中筛选出来的，其基本化学结构为S-亚硝基-N-乙酰青霉胺（ SNAP），激活非神经元乙酰胆碱（NNA）系统。SNPiP 治疗的小鼠表现出心输出量改善和舒张功能增强，但心率没有增加。NNA 激活作用包括增强缺血恢复能力、调节能量代谢偏好以及激活血管生成。在这里，我们对 SNPiP 治疗的小鼠心室进行转录组分析，以阐明 SNPiP 如何对心脏功能发挥有益作用。一项时程研究（SNPiP 给药后 24 小时和 48 小时）显示，SNPiP 最初诱导 Wnt 和 cGMP-蛋白激酶 G (PKG) 信号通路，同时上调参与心肌组织发育和催产素信号通路的基因。我们还观察到 SNPiP 治疗后糖酵解相关基因的富集，导致代谢从氧化磷酸化转变为糖酵解，这通过降低心脏葡萄糖含量同时维持 ATP 水平来表明。此外，SNPiP 显着上调心房钠尿肽 (ANP) 和肌磷脂 (SLN)，它们在钙处理和心脏功能中发挥着至关重要的作用。这些发现表明，基于本研究阐明的多效机制，SNPiP 可能具有治疗潜力。