AP-1 activation mediates post-natal cardiomyocyte maturation

Zhang, Hongjie; Pei, Lijuan; Ouyang, Zhaohui; Wang, Haocun; Chen, Xin; Jiang, Kai; Huang, Shiqi; Jiang, Rui; Xiang, Yaozu; Wei, Ke

doi:10.1093/cvr/cvac088

Cited by 17 publications

(6 citation statements)

References 50 publications

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“…Neonatal rat ventricular cardiomyocytes (NRVCs) were isolated from 1-day-old neonatal Sprague-Dawley rats (Shanghai Laboratory Animal Center, CAS) as previously described. 28 In brief, neonatal rat’s hearts were separated and dissociated in 0.25% trypsin (Gibco, 15090046) at 4 °C overnight. The next day, rat tissue was digested in 0.1% collagenase type ∥ (Worthington, LS004176) at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Tang

Feng

et al. 2023

Circulation

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BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. CONCLUSION: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

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Section: Methodsmentioning

confidence: 99%

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Tang

Feng

et al. 2023

Circulation

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“…The neonatal rat cardiomyocytes (NRCMs) were extracted according to the reference [ 28 ] and cultured in DMEM supplemented with 10% FBS in a humidified, 5% CO 2 /95% air atmosphere at 37 °C. The H9C2 cardiomyocytes were obtained from the American Type Culture Collection (ATCC, Manassas, VA, United States) and cultured in DMEM supplemented with 10% FBS in a humidified, 5% CO 2 /95% air atmosphere at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Effects of Malate Ringer's solution on myocardial injury in sepsis and enforcement effects of TPP@PAMAM-MR

et al. 2022

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Background Myocardial dysfunction played a vital role in organ damage after sepsis. Fluid resuscitation was the essential treatment in which Lactate Ringer's solution (LR) was commonly used. Since LR easily led to hyperlactatemia, its resuscitation effect was limited. Malate Ringer's solution (MR) was a new resuscitation crystal liquid. Whether MR had a protective effect on myocardial injury in sepsis and the relevant mechanism need to be studied. Methods The cecal ligation and puncture (CLP) inducing septic model and lipopolysaccharide (LPS) stimulating cardiomyocytes were used, and the cardiac function, the morphology and function of mitochondria were observed. The protective mechanism of MR on myocardial injury was explored by proteomics. Then the effects of TPP@PAMAM-MR, which consisted of the mitochondria- targeting polymer embodied malic acid, was further observed. Results Compared with LR, MR resuscitation significantly prolonged survival time, improved the cardiac function, alleviated the damages of liver, kidney and lung following sepsis in rats. The proteomics of myocardial tissue showed that differently expressed proteins between MR and LR infusion involved oxidative phosphorylation, apoptosis. Further study found that MR decreased ROS, improved the mitochondrial morphology and function, and ultimately enhanced mitochondrial respiration and promoted ATP production. Moreover, MR infusion decreased the expression of apoptosis-related proteins and increased the expression of anti-apoptotic proteins. TPP@PAMAM@MA was a polymer formed by wrapping l-malic acid with poly amido amine (PAMAM) modified triphenylphosphine material. TPP@PAMAM-MR (TPP-MR), which was synthesized by replacing the l-malic acid of MR with TPP@PAMAM@MA, was more efficient in targeting myocardial mitochondria and was superior to MR in protecting the sepsis-inducing myocardial injury. Conclusion MR was suitable for protecting myocardial injury after sepsis. The mechanism was related to MR improving the function and morphology of cardiomyocyte mitochondria and inhibiting cardiomyocyte apoptosis. The protective effect of TPP-MR was superior to MR.

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“…AP-1 is a family of TFs including four sub-families of hetero-and homo-dimers (Figure 3A), the Jun (c-Jun, JunB, JunD), Fos (c-Fos, FosB, Fra1, Fra2), BATF (BATF, BATF2, BATF3), and Maf (c-Maf, MafB, MafA) [109]. AP-1 TFs regulate a variety of cellular processes, such as cell division, apoptosis, senescence, differentiation, cell migration, immunity, oncogenic processes, and inflammation [110,111]. Signals of physiological and environmental stressors, such as growth factors, cytokines, tumor promoter molecules, and UV radiation, can activate AP-1 (Figure 3B).…”

Section: Activating Protein-1mentioning

confidence: 99%

Transcription Factors in Prostate Cancer: Insights for Disease Development and Diagnostic and Therapeutic Approaches

Silva,

Tambwe,

Mahfouz

et al. 2024

Genes

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Transcription factors (TFs) are proteins essential for the regulation of gene expression, and they regulate the genes involved in different cellular processes, such as proliferation, differentiation, survival, and apoptosis. Although their expression is essential in normal physiological conditions, abnormal regulation of TFs plays critical role in several diseases, including cancer. In prostate cancer, the most common malignancy in men, TFs are known to play crucial roles in the initiation, progression, and resistance to therapy of the disease. Understanding the interplay between these TFs and their downstream targets provides insights into the molecular basis of prostate cancer pathogenesis. In this review, we discuss the involvement of key TFs, including the E26 Transformation-Specific (ETS) Family (ERG and SPDEF), NF-κB, Activating Protein-1 (AP-1), MYC, and androgen receptor (AR), in prostate cancer while focusing on the molecular mechanisms involved in prostate cancer development. We also discuss emerging diagnostic strategies, early detection, and risk stratification using TFs. Furthermore, we explore the development of therapeutic interventions targeting TF pathways, including the use of small molecule inhibitors, gene therapies, and immunotherapies, aimed at disrupting oncogenic TF signaling and improving patient outcomes. Understanding the complex regulation of TFs in prostate cancer provides valuable insights into disease biology, which ultimately may lead to advancing precision approaches for patients.

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AP-1 activation mediates post-natal cardiomyocyte maturation

Cited by 17 publications

References 50 publications

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Effects of Malate Ringer's solution on myocardial injury in sepsis and enforcement effects of TPP@PAMAM-MR

Transcription Factors in Prostate Cancer: Insights for Disease Development and Diagnostic and Therapeutic Approaches

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