Roles of Glycogen Synthase Kinase-3 (GSK-3) in Cardiac Development and Heart Disease

Takahashi-Yanaga, Fumi

doi:10.7888/juoeh.40.147

Cited by 21 publications

(14 citation statements)

References 52 publications

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“…It has been shown that through these signaling pathways, transcriptional factors, such as nuclear factor of activated T-cell cytoplasmic 3 (NFATc3) and GATA4, are activated and translocate into the nucleus to stimulate transcription of several genes involved in cardiac hypertrophy [8,40]. GSK-3 directly inactivates NFATc3 and GATA4 by phosphorylating them [41]. Therefore, DM-celecoxib may also be able to suppress these hypertrophic signals evoked by isoprenaline by activating GSK-3.…”

Section: Discussionmentioning

confidence: 99%

2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation

Morishige

Takahashi-Yanaga

Ishikane

et al. 2019

Biochemical Pharmacology

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We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative that is unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating glycogen synthase kinase-3 (GSK-3) and prolonged the lifespan of heart failure mice with genetic dilated cardiomyopathy or transverse aortic constriction-induced left ventricular hypertrophy. However, it remained unclear how DM-celecoxib regulated structure and function of cardiomyocytes and cardiac fibroblasts involved in cardiac remodeling. In the present study, therefore, we investigated the effect of DM-celecoxib on isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation, because DM-celecoxib prevented isoprenaline-induced cardiac remodeling in vivo. DM-celecoxib suppressed isoprenaline-induced neonatal rat cardiomyocyte hypertrophy by the inhibition of Akt phosphorylation resulting in the activation of GSK-3 and the inhibition of β-catenin and mammalian target of rapamycin (mTOR). DM-celecoxib also suppressed the proliferation and the production of matrix metalloproteinase-2 and fibronectin of rat cardiac fibroblasts. Moreover, we found that phosphatase and tensin homolog on chromosome 10 (PTEN) could be a molecule to mediate the effect of DM-celecoxib on Akt. These results suggest that DM-celecoxib directly improves the structure and function of cardiomyocytes and cardiac fibroblasts and that this compound could be clinically useful for the treatment of β-adrenergic receptor-mediated maladaptive cardiac remodeling.

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Section: Discussionmentioning

confidence: 99%

2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation

Morishige

Takahashi-Yanaga

Ishikane

et al. 2019

Biochemical Pharmacology

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“…Regulates cardiac myocyte metabolism and controls cardiac hypertrophy (Potz et al, 2016;Takahashi-Yanaga, 2018) ATM…”

Section: Dna-pk Ser17mentioning

confidence: 99%

“…Growth factors stimulate MDM2 in multiple ways, including the downregulation of GSK3 and the activation of Akt. Interestingly, both GSK3 and Akt play an important role in controlling cardiac hypertrophy (Weeks et al, 2017;Takahashi-Yanaga, 2018).…”

Section: Growth Factor Responsive Kinasesmentioning

confidence: 99%

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Lam

Roudier

2019

Front. Cell Dev. Biol.

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The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.

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“…GSK-3β regulates cardiomyocyte and other types of cell proliferation and differentiation (Force and Woodgett, 2009;Woulfe et al, 2010), however, the underlying mechanism is largely unknown. The growth factors including FGF, epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) stimulate PI3K-Akt signaling and lead to Ser9 phosphorylation (inhibition) of GSK-3β (Cohen and Frame, 2001;Kaidanovich-Beilin and Woodgett, 2011;Takahashi-Yanaga, 2018). However, it is not clear whether dysregulated GSK-3β activity further modulates growth factor expression and secretion from cardiomyocytes under cardiac pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

Cardiomyocyte GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms

Yusuf

Qaisar

Al-Tamimi

et al. 2021

Preprint

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Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here we identify a potential role for glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPC proliferation that occurs after myocardial infarction (MI). Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable at two week post-MI, cKO mice displayed significantly preserved LV chamber and contractile function vs. control mice at four-weeks post-MI. Consistent with protective phenotypes, an increased percentage of c-kit positive cells (KPCs) were observed in the cKO hearts at four and six weeks post-MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic marker, CD45. Mechanistically, cardiomyocyte-GSK-3β profoundly suppresses the expression of growth factors (GFs), including basic-FGF angiopoietin-2, erythropoietin, stem cell factor (SCF), PDGF-BB, G-CSF, and VEGF, post-hypoxia. In conclusion, our findings strongly suggest that loss of cardiomyocyte-GSK-3β promotes cardiomyocyte and resident CPC proliferation post-MI. The induction of cardiomyocytes and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post-MI. A strategy to inhibit cardiomyocyte GSK-3β could be helpful for promotion of in-situ cardiac regeneration post-MI injury.

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Roles of Glycogen Synthase Kinase-3 (GSK-3) in Cardiac Development and Heart Disease

Cited by 21 publications

References 52 publications

2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation

2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Cardiomyocyte GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms

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