Atherosclerosis

2021

DOI: 10.1016/j.atherosclerosis.2021.11.001

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PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing the susceptibility for early atherosclerotic lesions in male apolipoprotein E knockout mice

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Robin A.F. Verwilligen

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et al.

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Arginine In Disease1

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Cited by 6 publications

(4 citation statements)

References 34 publications

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“…Recent studies have identi ed TP-064 as a selective and potent inhibitor of CARM1 function [19,20]. Consistent with previous observations that CARM1 acts as an NF-κB coactivator, our research showed that TP-064 reduced pro-in ammatory cytokine secretion [17,21].…”

Section: Discussionsupporting

confidence: 91%

CARM1 inhibitor TP064 attenuates endothelial cell dysfunction via inhibits inflammatory response in vitro model of subarachnoid hemorrhage

Zhang,

Zhang,

Liang

et al. 2024

Preprint

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Cerebral endothelial cell dysfunction plays a critical role in the pathophysiology of vascular injury subsequent to subarachnoid hemorrhage (SAH), yet the precise molecular mechanism remains largely speculative. Inflammation stands out as a pivotal contributor to an unfavorable prognosis post-SAH, with nuclear factor-κB (NF-κB) pathways being initiated and ultimately leading to inflammation activation and pro-inflammatory cytokine release following SAH. In this study, we explored the impact of the Coactivator-associated arginine methyltransferase 1 (CARM1) inhibitor TP-064 on inflammation using an in vitro SAH model. Exposure of endothelial cells to TP-064 resulted in a significant reduction in CAMR1 and NF-κB expression upon hemoglobin exposure. Similarly, endothelial cells treated with TP-064 following hemoglobin incubation exhibited decreased expression levels of intercellular adhesion molecule-1 (ICAM1), myeloperoxidase (MPO), and cytokine production including interleukin-1β (IL-1β), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α) in response to hemoglobin exposure. Moreover, subsequent investigations demonstrated that CARM1 transcriptionally regulates NF-κB via methylation. Additionally, TP-064 notably mitigated endothelial dysfunction. Collectively, our findings identify TP-064 as a CARM1 inhibitor targeting inflammation and neutrophil infiltration, offering new insights into therapeutic strategies for addressing endothelial cell dysfunction following SAH.

“…Recent studies have identi ed TP-064 as a selective and potent inhibitor of CARM1 function [19,20]. Consistent with previous observations that CARM1 acts as an NF-κB coactivator, our research showed that TP-064 reduced pro-in ammatory cytokine secretion [17,21].…”

Section: Discussionsupporting

confidence: 91%

CARM1 inhibitor TP064 attenuates endothelial cell dysfunction via inhibits inflammatory response in vitro model of subarachnoid hemorrhage

Zhang,

Zhang,

Liang

et al. 2024

Preprint

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Cerebral endothelial cell dysfunction plays a critical role in the pathophysiology of vascular injury subsequent to subarachnoid hemorrhage (SAH), yet the precise molecular mechanism remains largely speculative. Inflammation stands out as a pivotal contributor to an unfavorable prognosis post-SAH, with nuclear factor-κB (NF-κB) pathways being initiated and ultimately leading to inflammation activation and pro-inflammatory cytokine release following SAH. In this study, we explored the impact of the Coactivator-associated arginine methyltransferase 1 (CARM1) inhibitor TP-064 on inflammation using an in vitro SAH model. Exposure of endothelial cells to TP-064 resulted in a significant reduction in CAMR1 and NF-κB expression upon hemoglobin exposure. Similarly, endothelial cells treated with TP-064 following hemoglobin incubation exhibited decreased expression levels of intercellular adhesion molecule-1 (ICAM1), myeloperoxidase (MPO), and cytokine production including interleukin-1β (IL-1β), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α) in response to hemoglobin exposure. Moreover, subsequent investigations demonstrated that CARM1 transcriptionally regulates NF-κB via methylation. Additionally, TP-064 notably mitigated endothelial dysfunction. Collectively, our findings identify TP-064 as a CARM1 inhibitor targeting inflammation and neutrophil infiltration, offering new insights into therapeutic strategies for addressing endothelial cell dysfunction following SAH.

“…Similar to furamidine, the treatment of GSK3368715 significantly decreased I Ks activity without altering the shape of the I – V relationships or V 1/2 in HEK293T cells (Supporting Information: Figure ). In contrast to furamidine and GSK3368715, TP‐064, a potent and selective inhibitor of PRMT4 (Zhang et al, 2021) had no significant effect on I Ks activity in HEK293T cells (Supporting Information: Figure ). We then assessed whether furamidine modulates the methylation of KCNQ1 in cells.…”

Section: Resultsmentioning

confidence: 99%

Modulation of I_Ks channel–PIP₂ interaction by PRMT1 plays a critical role in the control of cardiac repolarization

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et al. 2022

Journal Cellular Physiology

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Recent studies have shown that protein arginine methyltransferase 1 (PRMT1) is highly expressed in the human heart, and loss of PRMT1 contributes to cardiac remodeling in the heart failure. However, the functional importance of PRMT1 in cardiac ion channels remains uncertain. The slow activating delayed rectifier K+ (IKs) channel is a cardiac K+ channel composed of KCNQ1 and KCNE1 subunits and is a new therapeutic target for treating lethal arrhythmias in many cardiac pathologies, especially heart failure. Here, we demonstrate that PRMT1 is a critical regulator of the IKs channel and cardiac rhythm. In the guinea pig ventricular myocytes, treatment with furamidine, a PRMT1‐specific inhibitor, prolonged the action potential duration (APD). We further show that this APD prolongation was attributable to IKs reduction. In HEK293T cells expressing human KCNQ1 and KCNE1, inhibiting PRMT1 via furamidine reduced IKs and concurrently decreased the arginine methylation of KCNQ1, a pore‐forming α‐subunit. Evidence presented here indicates that furamidine decreased IKs mainly by lowering the affinity of IKs channels for the membrane phospholipid, phosphatidylinositol 4,5‐bisphosphate (PIP2), which is crucial for pore opening. Finally, applying exogenous PIP2 to cardiomyocytes prevented the furamidine‐induced IKs reduction and APD prolongation. Taken together, these results indicate that PRMT1 positively regulated IKs activity through channel–PIP2 interaction, thereby restricting excessive cardiac action potential.

“… 225 Administration of the PRMT4 inhibitor TP-064 in a mouse model of atherosclerotic cardiovascular disease can induce a decrease in monocyte tumor necrosis factor-α (TNF-α) secretion, downregulate the gene expression of the glycogen metabolism-related protein G6pc in the liver, and reduce plasma triglyceride levels, exerting regulatory effects from inflammatory and metabolic pathways. 226 …”

Section: Arginine (Arg)mentioning

confidence: 99%

“…225 Administration of the PRMT4 inhibitor TP-064 in a mouse model of atherosclerotic cardiovascular disease can induce a decrease in monocyte tumor necrosis factor-α (TNF-α) secretion, downregulate the gene expression of the glycogen metabolism-related protein G6pc in the liver, and reduce plasma triglyceride levels, exerting regulatory effects from inflammatory and metabolic pathways. 226 Inhibitors targeting PRMTs are being developed and experimentally tested. Arg methylase inhibitors (AMIs), symmetric sulfonated urea, specifically inhibit PRMT activity and, in a rat model, cyclooxygenase-2 (COX-2) expression and suppress inflammation.…”

Section: Arginine In Diseasementioning

confidence: 99%

Amino acid metabolism in health and disease

Ling,

Jiang,

Ru

et al. 2023

Sig Transduct Target Ther

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Amino acids are the building blocks of protein synthesis. They are structural elements and energy sources of cells necessary for normal cell growth, differentiation and function. Amino acid metabolism disorders have been linked with a number of pathological conditions, including metabolic diseases, cardiovascular diseases, immune diseases, and cancer. In the case of tumors, alterations in amino acid metabolism can be used not only as clinical indicators of cancer progression but also as therapeutic strategies. Since the growth and development of tumors depend on the intake of foreign amino acids, more and more studies have targeted the metabolism of tumor-related amino acids to selectively kill tumor cells. Furthermore, immune-related studies have confirmed that amino acid metabolism regulates the function of effector T cells and regulatory T cells, affecting the function of immune cells. Therefore, studying amino acid metabolism associated with disease and identifying targets in amino acid metabolic pathways may be helpful for disease treatment. This article mainly focuses on the research of amino acid metabolism in tumor-oriented diseases, and reviews the research and clinical research progress of metabolic diseases, cardiovascular diseases and immune-related diseases related to amino acid metabolism, in order to provide theoretical basis for targeted therapy of amino acid metabolism.

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