Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin

Wo, Da; Peng, Jie; Ren, Dan‐ni; Qiu, Liman; Chen, Jingxiao; Zhu, Yang; Yan, Yingjing; Yan, Hongwei; Wu, Jian; Eglitis, Martin A.; Zhong, Tao; Chen, Yihan; Liu, Zhongmin; Liu, Shangfeng; Ao, Luoquan; Liu, Zhenping; Jiang, Cizhong; Peng, Jun; Zou, Yunzeng; Qian, Qirong; Zhu, Weidong

doi:10.1161/circulationaha.116.024441

Cited by 74 publications

(64 citation statements)

References 57 publications

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“…IGFBP-4 acted as a cardiogenic growth factor by inhibiting Wnt signalling 449 (Zhu, et al 2008), and it induced cardiomyocyte differentiation from stem cells by inhibiting β-450 catenin signalling (Xue, et al 2014). IGFBP-4 injection in rats also decreased ischaemic injury after 451 myocardial infarction by inhibiting β-catenin activation (Wo, et al 2016). A number of other 452 studies also suggested IGF-independent actions of IGFBP-4 but the underlying mechanisms were 453 not studied (Perks, et al 1999;Singh, et al 1994;Wright, et al 2002).…”

Section: Igf-independent Actions 447mentioning

confidence: 97%

40 YEARS OF IGF1: IGF-binding proteins

Bach

2018

Journal of Molecular Endocrinology

204

111

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Insulin-like growth factor binding proteins (IGFBPs) 1-6 bind IGFs but not insulin with high affinity. They were initially identified as serum carriers and passive inhibitors of IGF actions.However, subsequent studies showed that, although IGFBPs inhibit IGF actions in many circumstances, they may also potentiate these actions. IGFBPs are widely expressed in most tissues, and they are flexible endocrine and autocrine/paracrine regulators of IGF activity, which is essential for this important physiological system. More recently, individual IGFBPs have been shown to have IGF-independent actions. Mechanisms underlying these actions include (i) interaction with non-IGF proteins in compartments including the extracellular space and matrix, the cell surface and intracellularly; (ii) interaction with and modulation of other growth factor pathways including EGF, TGF-β and VEGF; and (iii) direct or indirect transcriptional effects following nuclear entry of IGFBPs. Through these IGF-dependent and IGF-independent actions, IGFBPs modulate essential cellular processes including proliferation, survival, migration, senescence, autophagy and angiogenesis. They have been implicated in a range of disorders including malignant, metabolic, neurological and immune diseases. A more complete understanding of their cellular roles may lead to the development of novel IGFBP-based therapeutic opportunities.Page 2 of 51 3The somatomedin hypothesis, which postulated that growth hormone activity was mediated by a 1 serum factor, was published in 1957 (Salmon and Daughaday 1957). In the 1960s, several 2 circulating somatomedin activities were identified and attributed to peptides sized 5~8 kDa that had 3 both growth promoting and insulin-like metabolic effects. A paradox of these early observations 4 was that normoglycaemia was maintained in vivo despite the circulating concentrations of 5 somatomedins being sufficient to cause profound hypoglycaemia. Following the purification of 6 these small somatomedin peptides, it was observed that almost all of the circulating somatomedin 7 activity was found in a number of chromatographic peaks with apparent molecular weights greater 8 than 30~40 kDa and further studies indicated that this was due to binding by plasma binding 9proteins (Hintz and Liu 1977;Megyesi, et al. 1975;Zapf, et al. 1975). The apparent hypoglycaemia 10 paradox could then be resolved if somatomedin activity was inhibited by association with these 11 binding proteins. Of note, these early studies already demonstrated that insulin did not bind to these 12 proteins. 13 14In the following years, the somatomedin activities were identified as IGF-I and IGF-II, and they 15 were sequenced and cloned. IGF binding proteins (IGFBPs) 1-3 were the first to be identified and 16 purified, with IGFBPs 4-6 being subsequently described (Rajaram, et al. 1997;Rechler 1993). By 17 the early 1990s, all six members of this high affinity IGFBP family had been cloned and a number 18 of key structural and sequence similarities identified. Addition...

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Section: Igf-independent Actions 447mentioning

confidence: 97%

40 YEARS OF IGF1: IGF-binding proteins

Bach

2018

Journal of Molecular Endocrinology

204

111

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“…The canonical Wnt/β-catenin signaling is negatively regulated by a range of molecules, which act either extracellularly by affecting the interaction between Wnt ligands and its receptor complex, or intracellularly by interfering with signal transduction (Chen et al, 2009; Paluszczak et al, 2015; Wo et al, 2016). Dkk1 has been regarded as one of the extracellular antagonist of canonical Wnt/β-catenin signaling (Zhou et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Pentazocine Protects SN4741 Cells Against MPP+-Induced Cell Damage via Up-Regulation of the Canonical Wnt/β-Catenin Signaling Pathway

Wang

et al. 2017

Front. Aging Neurosci.

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The Wnt/β-catenin signaling pathway has been linked to many neurodegenerative diseases including Parkinson’s disease (PD). A glycoprotein named Dickkopf-1 (Dkk1) can combine with the receptor complex on cell membrane to inhibit Wnt/β-catenin signaling. Opioids, a series of compounds including morphine, fentanyl and pentazocine, have been reported to contribute to the up-regulation of Wnt/β-catenin signaling. Naloxone is an antagonist that has been used as an antidote to opioids through mu-opioid receptor. 1-methyl-4-phenylpyridinium (MPP+), which serves as a selective toxin for dopaminergic neurons, has been used to create experimental models of PD. In our study, we examined the protective effects of pentazocine against MPP+-induced cell death in the nigral dopaminergic cell line, SN4741 and tried to elucidate the molecular mechanisms underlying such protective effects. The data showed that pretreatment with pentazocine significantly rescued the SN4741 cell against MPP+. Moreover, the MPP+-exposed SN4741 cells exhibited a down-regulation of β-catenin, which could be restored by treatment with pentazocine. However, Dkk1 but not naloxonewas associated with the abrogation of protective effect of pentazocine. These results suggest that pentazocine alleviates MPP+-induced SN4741 cells apoptosis via the up-regulation of canonical Wnt/β-catenin signaling.

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“…The role of the LRP coreceptors in infarct healing has been studied more extensively. Induction of MI in mice deficient in LRP5 resulted in an increase in infarct size (Borrell-Pages et al, 2016) but no change in infarct area or cardiac function, as observed when LRP5 was specifically deleted in CMs (Wo et al, 2016). In several studies, the effect of DKK proteins, endogenous antagonists of LRP proteins, on infarct healing was addressed.…”

Section: Wnt Signalingmentioning

confidence: 99%

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

Blankesteijn

2019

Mol Pharmacol

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Myocardial infarction is a frequent cardiovascular event and a major cause for cardiomyocyte loss. In adult mammals, cardiomyocytes are traditionally considered to be terminally differentiated cells, unable to proliferate. Therefore, the woundhealing response in the infarct area typically yields scar tissue rather than newly formed cardiomyocytes. In the last decade, several lines of evidence have challenged the lack of proliferative capacity of the differentiated cardiomyocyte: studies in zebrafish and neonatal mammals have convincingly demonstrated the regenerative capacity of cardiomyocytes. Moreover, multiple signaling pathways have been identified in these models that-when activated in adult mammalian cardiomyocytes-can reactivate the cell cycle in these cells. However, cardiomyocytes frequently exit the cell cycle before symmetric division into daughter cells, leading to polyploidy and multinucleation. Now that there is more insight into the reactivation of the cell cycle machinery, other prerequisites for successful symmetric division of cardiomyocytes, such as the control of sarcomere disassembly to allow cytokinesis, require more investigation. This review aims to discuss the signaling pathways involved in cardiomyocyte proliferation, with a specific focus on wingless/int-1 protein signaling. Comparing the conflicting results from in vitro and in vivo studies on this pathway illustrates that the interaction with other cells and structures around the infarct is likely to be essential to determine the outcome of these interventions. The extensive crosstalk with other pathways implicated in cardiomyocyte proliferation calls for the identification of nodal points in the cell signaling before cardiomyocyte proliferation can be moved forward toward clinical application as a cure of cardiac disease. SIGNIFICANCE STATEMENT Evidence is mounting that proliferation of pre-existing cardiomyocytes can be stimulated to repair injury of the heart. In this review article, an overview is provided of the different signaling pathways implicated in cardiomyocyte proliferation with emphasis on wingless/int-1 protein signaling, crosstalk between the pathways, and controversial results obtained in vitro and in vivo.

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Opposing Roles of Wnt Inhibitors IGFBP-4 and Dkk1 in Cardiac Ischemia by Differential Targeting of LRP5/6 and β-catenin

Abstract: Our findings reveal previously unidentified dual roles of LRP5/6 involved in the cardiomyocyte response to ischemic injury. These findings suggest new therapeutic strategies in ischemic heart disease by fine-tuning LRP5/6 and β-catenin signaling within the Wnt/β-catenin pathway.

Cited by 74 publications

References 57 publications

40 YEARS OF IGF1: IGF-binding proteins

40 YEARS OF IGF1: IGF-binding proteins

Pentazocine Protects SN4741 Cells Against MPP+-Induced Cell Damage via Up-Regulation of the Canonical Wnt/β-Catenin Signaling Pathway

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

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