Diminished arachidonate 5-lipoxygenase perturbs phase separation and transcriptional response of Runx2 to reverse pathological ventricular remodeling

Xie, Saiyang; Chen, Mengya; Fang, Wenxi; Liu, Shiqiang; Wu, Qin; Liu, Chen; Xing, Yun; Shi, Wenke; Xu, Man; Zhang, Min; Chen, Si; Zeng, Xiaofeng; Wang, Shasha; Deng, Wei; Tang, Qi‐Zhu

doi:10.1016/j.ebiom.2022.104359

Cited by 14 publications

(11 citation statements)

References 62 publications

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“…The 8-week-old male mice were acclimated in a quarantine room for 1 week before the subsequent experiments. In the TAC surgical induce model of pathological myocardial remodeling under chronic pressure overload, all the male mice injected with Sema and its vehicle underwent TAC surgery or sham surgery as a control group 77 . Sema was purchased from the Master of Bioactive Molecules, and was used based on available studies and biopotency conversions 78 , 79 .…”

Section: Methodsmentioning

confidence: 99%

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Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis

Ma,

Kong,

Guo

et al. 2024

Nat Commun

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Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.

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Section: Methodsmentioning

confidence: 99%

“…Echocardiography was performed at 4 or 8 weeks after TAC. Echocardiography was analyzed with a 10-MHz linear array ultrasound transducer equipped with a 30-MHz probe (Vevo 3100 system Visual Sonics) 77 , 80 . First, the mice were anaesthetised with a mixture of 4% isoflurane and 0.5 L/min oxygen.…”

Section: Methodsmentioning

confidence: 99%

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis

Ma,

Kong,

Guo

et al. 2024

Nat Commun

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“…In addition to its interaction with euchromatin and NFκB family members, a direct interaction of 5-LO and RUNX2, a transcription factor that plays an important role in differentiation, growth processes and cell cycle regulation, was recently detected [57]. In patients suffering from cardiac hypertrophy and heart failure, 5-LO protein levels are significantly increased while levels of the 5-LO product 5-HETE were hardly changed.…”

Section: -Lo As Strand (Shuttling Transcriptional Regulator and Non-d...mentioning

confidence: 99%

The role of human 5-Lipoxygenase (5-LO) in carcinogenesis - a question of canonical and non-canonical functions

Kahnt,

Häfner,

Steinhilber

2024

Oncogene

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Abstract5-Lipoxygenase (5-LO), a fatty acid oxygenase, is the central enzyme in leukotriene (LT) biosynthesis, potent arachidonic acid-derived lipid mediators released by innate immune cells, that control inflammatory and allergic responses. In addition, through interaction with 12- and 15-lipoxgenases, the enzyme is involved in the formation of omega-3 fatty acid-based oxylipins, which are thought to be involved in the resolution of inflammation. The expression of 5-LO is frequently deregulated in solid and liquid tumors, and there is strong evidence that the enzyme plays an important role in carcinogenesis. However, global inhibition of LT formation and signaling has not yet shown the desired success in clinical trials. Curiously, the release of 5-LO-derived lipid mediators from tumor cells is often low, and the exact mechanism by which 5-LO influences tumor cell function is poorly understood. Recent data now show that in addition to releasing oxylipins, 5-LO can also influence gene expression in a lipid mediator-independent manner. These non-canonical functions, including modulation of miRNA processing and transcription factor shuttling, most likely influence cancer cell function and the tumor microenvironment and might explain the low clinical efficacy of pharmacological strategies that previously only targeted oxylipin formation and signaling by 5-LO. This review summarizes the canonical and non-canonical functions of 5-LO with a particular focus on tumorigenesis, highlights unresolved issues, and suggests future research directions.

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“…Cancer cells undergo metabolic remodeling, which provides the ATP and macromolecules needed for rapid cell growth, division, and survival. AA and its metabolites are associated with the occurrence of a variety of tumors, and the importance of alterations in fatty acid metabolism in cancer cells has attracted much attention 240–242 . In addition to being structural components of the membrane matrix, fatty acids are also important secondary messengers, and different secondary metabolites of fatty acids can participate in the occurrence and development of tumors 243,244 .…”

Section: Aa Metabolism In Human Health and Diseasesmentioning

confidence: 99%

“…AA and its metabolites are associated with the occurrence of a variety of tumors, and the importance of alterations in fatty acid metabolism in cancer cells has attracted much attention. 240 , 241 , 242 In addition to being structural components of the membrane matrix, fatty acids are also important secondary messengers, and different secondary metabolites of fatty acids can participate in the occurrence and development of tumors. 243 , 244 We briefly summarized the mechanisms of AA and its metabolism‐related enzymes in regulating key signaling pathways, regulating gene expression, and influencing cell apoptosis (Figure 5 ).…”

Section: Aa Metabolism In Human Health and Diseasesmentioning

confidence: 99%

Arachidonic acid metabolism in health and disease

Zhang,

Liu,

Sun

et al. 2023

MedComm

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Arachidonic acid (AA), an n‐6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays essential biochemical roles, as it is the direct precursor of bioactive lipid metabolites of eicosanoids such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acid obtained from three distinct enzymatic metabolic pathways: the cyclooxygenase pathway, lipoxygenase pathway, and cytochrome P450 pathway. AA metabolism is involved not only in cell differentiation, tissue development, and organ function but also in the progression of diseases, such as hepatic fibrosis, neurodegeneration, obesity, diabetes, and cancers. These eicosanoids are generally considered proinflammatory molecules, as they can trigger oxidative stress and stimulate the immune response. Therefore, interventions in AA metabolic pathways are effective ways to manage inflammatory‐related diseases in the clinic. Currently, inhibitors targeting enzymes related to AA metabolic pathways are an important area of drug discovery. Moreover, many advances have also been made in clinical studies of AA metabolic inhibitors in combination with chemotherapy and immunotherapy. Herein, we review the discovery of AA and focus on AA metabolism in relation to health and diseases. Furthermore, inhibitors targeting AA metabolism are summarized, and potential clinical applications are discussed.

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Diminished arachidonate 5-lipoxygenase perturbs phase separation and transcriptional response of Runx2 to reverse pathological ventricular remodeling

Cited by 14 publications

References 62 publications

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis

The role of human 5-Lipoxygenase (5-LO) in carcinogenesis - a question of canonical and non-canonical functions

Arachidonic acid metabolism in health and disease

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