Dickkopf-3 attenuates pressure overload-induced cardiac remodelling

Zhang, Yan; Liu, Yu; Zhu, Xiashi; Zhang, Xiaodong; Jiang, Ding‐Sheng; Bian, Zhou‐Yan; Zhang, Xiaofei; Chen, Ke; Wei, Xiang; Gao, Lu; Zhu, Lihua; Yang, Qinglin; Fan, Guo-Chang; Lau, Wayne Bond; Ma, Xin‐Liang; Li, Hongliang

doi:10.1093/cvr/cvu004

Cited by 69 publications

(73 citation statements)

References 40 publications

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“…erties (Fiedler et al, 2002;Sanbe et al, 2003; Li et al, 2010a,b;Yan et al, 2011). Based on these critical molecules, numerous dominant signalling pathways regulating cardiac remodelling have been revealed, particularly the GPCR-calcineurin-NFAT pathway, Ras-MAPK signalling, and the IGF-I-PI3K-Akt/PKBmammalian target of rapamycin/GSK3β axis (Heineke and Molkentin, 2006;Huang et al, 2010; Chen et al, 2013b;Jiang et al, 2014e;Liu et al, 2014;Zhang et al, 2014d). Experimental evidence from our laboratory and others' indicated the involvement of IRF1, IRF3, IRF4, IRF5, IRF7, IRF8 and IRF9 in the initiation and development of cardiac remodelling.…”

Section: Figurementioning

confidence: 99%

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

Zhang

Jiang

2015

British J Pharmacology

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The family of interferon regulatory factors (IRFs) consists of nine members (IRF1-IRF9) in mammals. They act as transcription factors for the interferons and thus exert essential regulatory functions in the immune system and in oncogenesis. Recent clinical and experimental studies have identified critically important roles of the IRFs in cardiovascular diseases, arising from their participation in divergent and overlapping molecular programmes beyond the immune response. Here we review the current knowledge of the regulatory effects and mechanisms of IRFs on the immune system. The role of IRFs and their potential molecular mechanisms as novel stress sensors and mediators of cardiovascular diseases are highlighted. LINKED ARTICLESThis article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-23 Abbreviations ATF3, activating transcription factor 3; CBP, CREB-binding protein; cDCs, conventional dendritic cells; CLL, chronic lymphocytic leukaemia; CMPs, common myeloid progenitor cells; CREB, cAMP-responsive element-binding protein; Dock2, dedicator of cytokinesis 2; dsRNA, double-stranded RNA; ECM, extracellular matrix; ET-1, endothelin-1; GSK3β, glycogen synthase kinase 3β; GWAS, genome-wide association studies; HATs, histone acetyltransferases; HDACs, histone deacetylases; I/R, ischaemia/reperfusion; IAD, IRF-associated domain; IFN, interferon ; IGF-I, insulin-like growth factor I; iNOS, inducible NOS; IRFs, interferon regulatory factors; MAVS, mitochondrial antiviral signalling protein; MDA5, melanoma differentiation-associated gene 5; MyD88, myeloid differentiation primary-response protein 88; PCAF, p300/CBP-associated factor; pDCs, plasma cytoid dendritic cells; PRR, pattern recognition receptor; RIG-I, retinoic acid-inducible gene I; SLE, systemic lupus erythematosus; SRF, serum response factor; TAD, transcription activation domain; TBK1, TANK-binding kinase 1; TG, transgene; TIRAP, TIR domain-containing adaptor protein; TLRs, Toll-like receptors; TRAF, TNF receptor-associated factor; TRAM, TRIF-related adaptor molecule; TRIF, TIRAP-inducing IFN-β; Tyk2, tyrosine kinase 2; VSMCs, vascular smooth muscle cells Tables of Links Introduction and backgroundThe interferon regulatory factor (IRF) family was first described as transcriptional regulators of the type I interferon (IFN) system. Since 1988, when the first IRF was identified (Miyamoto et al., 1988), most studies of IRFs have focused on their functions in immunity. Abnormalities in IRFs are associated with changes in both innate and adaptive immune responses to cellular and environmental stimuli in a wide variety of pathways. Now, more recent evidence has revealed the remarkable contributions of IRFs to other diseases, such as cardiovascular diseases Jiang et al., 2014d;Zhang et al., 2014a), metabolic diseases (Eguchi et al., 2008;2011; Wang et al., 2013c,d;2014) and oncogenesis (Yanai et al., 2012). In this review, as docume...

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Section: Figurementioning

confidence: 99%

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

Zhang

Jiang

2015

British J Pharmacology

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“…[152][153][154] The orchestrated signal transduction events recognize injurious stimuli, induce the structural and functional changes in regulators, and ultimately reactivate fetal gene, promote protein synthesis, and increase cell size. 155,156 Pathological hypertrophy typically involves the reprogramming of a myriad of signaling events, such as calcineurin-nuclear factor of activated T cells, insulin-like growth factor-I-phosphatidylinositol 3-kinase-AKT, and MAPK signaling. 149,157 In addition, microRNAs (miRNAs) participate in the development of cardiac hypertrophy, heart failure, and hypertension.…”

Section: Irfs In Cardiac Hypertrophy and Hypertensionmentioning

confidence: 99%

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

Zhang

2015

Hypertension

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“…17 However, it found that Dkk3 expression was downregulated in the left ventricle myocardial samples from DCM patients in end-stage heart failure. 18 These results suggest that Dkk3 could be upregulated in compensation stage and downregulated in the decompensation stage of heart failure.…”

Section: Discussionmentioning

confidence: 85%

“…15,16 Dkk3 expression was increased in the afterloaded right ventricular (RV) 17 and participated in aortic bandinginduced cardiac hypertrophy via regulation of ASK-1-JNK/ p38. 18 Most of the knowledge about Dkk3 with regard to Wnt signaling comes from the study of cancers; Dkk3 can be an activator or an inhibitor of the canonical pathway, 5,8,13,[19][20][21][22][23][24] which is strictly context-dependent. However, whether and how Dkk3 interferes with Wnt signaling in the heart tissues has not been systematically examined thus far.…”

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Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway

Bao

Dong

et al. 2016

Laboratory Investigation

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To date, the role of Dickkopf 3 (Dkk3) on the pathogenesis of familial dilated cardiomyopathy (FDCM), and whether and how Dkk3 interferes with Wnt signaling in heart tissues remains unknown. Here, we demonstrate that strong Dkk3 expression was markedly downregulated in adult hearts from WT mice, and Dkk3 expression was upregulated suddenly in hearts from DCM mouse models. Using Dkk3 transgenic and knockout mice, as well as cTnT R141W transgenic mice, which manifests progressive chamber dilation and contractile dysfunction and has pathologic phenotypes similar to human DCM patients, we determined that transgenic expression of Dkk3 increased survival rate, improved cardiac morphology breakage and dysfunction, and ameliorated cardiac pathological changes in the cTnT R141W mice. In contrast, Dkk3 knockout reduced the survival rate and aggravated the pathological phenotypes of the cTnT R141W mice. The protective effects of Dkk3 appeared clearly at 3 months of age, peaked at 6 months of age, and decreased at 10 months of age in the cTnT R141W mice. Furthermore, we determined that Dkk3 upregulated Dvl1 (Dishevelled 1) and key proteins of the canonical Wnt pathway (cytoplasmic and nuclear β-catenin, c-Myc, and Axin2) and downregulated key proteins of the noncanonical Wnt pathway (c-Jun N-terminal kinase (JNK), Ca 2+ /calmodulin-dependent protein kinase II (CAMKII), and histone deacetylase 4 (HDAC4)). In contrast, Dkk3 knockout reversed these changes in the cTnT R141W mice. In summary, Dkk3 could prevent FDCM development in mice, especially in the compensatory stage, and probably through activation of the canonical and inhibition of the noncanonical Wnt pathway, which suggested that Dkk3 could serve as a therapeutic target for the treatment of cardiomyopathy and heart failure.

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Dickkopf-3 attenuates pressure overload-induced cardiac remodelling

Abstract: Taken together, our findings indicate that DKK3 acts as a cardioprotective regulator of pathological cardiac hypertrophy and that this function largely occurs via the regulation of ASK1-JNK/p38 signalling.

Cited by 69 publications

References 40 publications

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway

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