S-Nitroso-N-Pivaloyl-D-Penicillamine, a novel non-neuronal ACh system activator, modulates cardiac diastolic function to increase cardiac performance under pathophysiological conditions

Oikawa, Shino; Kitagawa, Yuko; Mano, Asuka; Nakamura, Shigeo; Kakinuma, Yoshihiko

doi:10.1016/j.intimp.2020.106459

Cited by 6 publications

(12 citation statements)

References 23 publications

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“…This compound releases NO for longer than traditional NO donors, indicating its potential to enhance cardiac function. Indeed, in vivo experiments with SNPiP-treated mice have demonstrated improved diastolic function without tachycardia, leading to enhanced cardiac output without an increase in heart rate which supports our hypothesis that the NNCCS plays a crucial role in sustaining cardiac functions, including potentiating resilience to ischemia, modulating energy metabolism preference, and activating angiogenesis [12]. SNPiP also improved impaired cardiac function in db/db hearts [13], suggesting its potential use as a therapeutic agent to activate the NNCCS and modulate cardiac function.…”

Section: Introductionsupporting

confidence: 82%

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Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-nitroso-N-pivaloyl-D-penicillamine (SNPiP): Implications for Improved Diastolic Function and Cardiac Performance

Takenaka

Hirasaki

Bono

et al. 2023

Preprint

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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 SNPiP-treated samples, indicating a metabolic shift from oxidative phosphorylation to glycolysis following SNPiP administration in the hearts. 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.

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Section: Introductionsupporting

confidence: 82%

“…We previously reported the effects of SNPiP, a novel NO donor and NNCCS activator, on cardiac function [12]. This compound releases NO for longer than traditional NO donors, indicating its potential to enhance cardiac function.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-nitroso-N-pivaloyl-D-penicillamine (SNPiP): Implications for Improved Diastolic Function and Cardiac Performance

Takenaka

Hirasaki

Bono

et al. 2023

Preprint

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“…In these studies, the effect of SNPiP on cardiac function was most pronounced 48 and 72 hours after administration. 12,13 Table 1 shows the effects of SNPiP on cardiac functions at 72 hours. SNPiP significantly increased end-systolic pressure, end-diastolic volume, stroke volume, and CO ( # P < 0.01, $ P < 0.05).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, in vivo experiments with SNPiP-treated mice have demonstrated improved diastolic function without tachycardia, leading to enhanced cardiac output (CO) without an increase in HR, which supports our hypothesis that the NNCCS plays a crucial role in sustaining cardiac functions, including potentiating resilience to ischemia, modulating energy metabolism preference, and activating angiogenesis. 12 SNPiP also improved impaired cardiac function in db / db hearts, 13 suggesting its potential use as a therapeutic agent to activate the NNCCS and modulate cardiac function. It has been reported that SNPiP gradually elevates the intracellular levels of cyclic guanosine monophosphate (cGMP) and NO levels in H9c2 and HEK293 cells, 12 which in turn upregulate choline acetyltransferase and increase ACh synthesis.…”

Section: Introductionmentioning

confidence: 99%

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

Takenaka,

Hirasaki,

Bono

et al. 2024

Journal of Cardiovascular Pharmacology

Self Cite

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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.

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“…Several related nitrosothiols are also claimed. For the peer review companion papers see Oikawa et al [10,11] Published: Mutations in matriptase-2, a liver cell-surface serine protease, cause iron-refractory iron deficiency anemia because expression of the peptide hormone hepcidin is not downregulated by matriptase suppression of the Bmp/Smad pathway [12]. Conversely, relative overactivity of matriptase-2 -as for example, in hemochromatosis -leads to genetic or acquired diseases of iron overload [13], which is why interest in designing small-molecule matriptase inhibitors has surged recently [14].…”

Section: Wo/2020/067485mentioning

confidence: 99%

Patent Highlights April–May 2020

Mucke¹

2020

Pharm. Pat. Anal.

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S-Nitroso-N-Pivaloyl-D-Penicillamine, a novel non-neuronal ACh system activator, modulates cardiac diastolic function to increase cardiac performance under pathophysiological conditions

Cited by 6 publications

References 23 publications

Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-nitroso-N-pivaloyl-D-penicillamine (SNPiP): Implications for Improved Diastolic Function and Cardiac Performance

Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-nitroso-N-pivaloyl-D-penicillamine (SNPiP): Implications for Improved Diastolic Function and Cardiac Performance

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

Patent Highlights April–May 2020

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