A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective

Yu, Baoqi; Kiechl, Stefan; Qi, Dan; Wang, Xiaochong; Song, Yanting; Weger, Siegfried; Mayr, Agnes; Bras, Alexandra Le; Karamariti, Eirini; Zhang, Zhongyi; Barrantes, Iván del Barco; Niehrs, Christof; Schett, Georg; Hu, Yanhua; Wang, Wen; Willeit, Johann; Qu, Aijuan; Xu, Qingbo

doi:10.1161/circulationaha.117.027690

Cited by 56 publications

(63 citation statements)

References 69 publications

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“…DKK3 is strongly expressed in endothelial, smooth muscle cells, and platelets 21‐22,27. Consistent with this finding, DKK3 expression partially co‐localized with cavernous endothelial cells.…”

Section: Discussionsupporting

confidence: 76%

“…DKK3 is also known to bind CXCR7 and induce chemotaxis of stem cell antigen 1 + (Sca‐1 + ) vascular progenitor cells, and promote reendothelialization in a tissue‐engineered vascular graft model 28. Moreover, targeted deletion of the DKK3 gene delayed reendothelialization in ApoE ‐/‐ mice with femoral artery wire injury 21. These results support the crucial function of DKK3 in mediating vascular endothelial integrity.…”

Section: Discussionmentioning

confidence: 60%

“…Consistent with this finding, DKK3 expression partially co‐localized with cavernous endothelial cells. DKK3 was reported to enhance the migration of human umbilical vein endothelial cells by activating the non‐canonical Wnt pathway 21. DKK3 is also known to bind CXCR7 and induce chemotaxis of stem cell antigen 1 + (Sca‐1 + ) vascular progenitor cells, and promote reendothelialization in a tissue‐engineered vascular graft model 28.…”

Section: Discussionmentioning

confidence: 99%

“…Recent clinical trial suggests a protective role of DKK3 in atherogenesis. In a prospective population‐based study, plasma DKK3 concentrations showed an inverse correlation with intima‐media thickness of common carotid artery 21. Serum DKK3 levels were lower in patients with symptoms of unstable angina than those with stable angina 22.…”

Section: Introductionmentioning

confidence: 97%

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Intracavernous delivery of Dickkopf3 gene or peptide rescues erectile function through enhanced cavernous angiogenesis in the diabetic mouse

et al. 2020

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Background Severe peripheral angiopathy in patients with diabetes is a major contributing factor for low response rate to phosphodiesterase‐5 inhibitors. Objectives To examine whether and how Dickkopf3 (DKK3), a secreted modulator of the Wnt pathway that known to be involved in endothelial cell repair and vascular progenitor cell migration, restores erectile function in diabetic mice. Methods Eight‐week‐old C57BL/6 mice received intraperitoneal injections of streptozotocin (50 mg/kg for 5 days). Eight weeks after the diabetes was induced, the efficacy of DKK3 was determined by three independent experiments: experiment 1 (DKK3 peptide [5 μg in 20 μL PBS]); experiment 2 (DKK3 plasmid DNA with electroporation [10, 40, or 100 μg in 20 μL PBS, respectively]); and experiment 3 (DKK3 adenovirus [1 × 107, 1 × 108, 1 × 109 virus particles per 20 μL, respectively]). Erectile function was measured by electrical stimulation of the cavernous nerve one week (for peptide) or two weeks (for genes) after treatment. The angiogenic activity of DKK3 was determined in diabetic penis in vivo and in primary cultured mouse cavernous endothelial cells (MCECs) in vitro. Results The cavernous expression of DKK3 protein was significantly lower in the diabetic mice than in controls. DKK3 peptide or adenovirus significantly improved erectile function in diabetic mice (70% of the control values). DKK3 adenovirus profoundly restored cavernous endothelial cell and pericyte contents and increased endothelial junction proteins in diabetic mice in vivo. DKK3 peptide induced upregulation of angiogenic factors (angiopoietin‐1, vascular endothelial growth factor, and basic fibroblast growth factor) and accelerated tube formation in MCECs cultivated under the high‐glucose condition in vitro. Conclusion DKK3 restored cavernous vascular integrity and improved erectile function in diabetic mice. Therapeutic cavernous angiogenesis by the use of DKK3 will be a promising therapeutic strategy to treat diabetic erectile dysfunction.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Intracavernous delivery of Dickkopf3 gene or peptide rescues erectile function through enhanced cavernous angiogenesis in the diabetic mouse

et al. 2020

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“…DKK3 has been reported to inhibit inflammation through the noncanonical Wnt signaling pathway in a model of atherosclerosis. This mechanism promoted reendothelialization and induced endothelial cell migration (50). Furthermore, DKK3 has also been observed in a cardioprotective model to interrupt the ASK1-JNK/p38 signaling cascades (9).…”

Section: Discussionmentioning

confidence: 95%

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

Yang

Nowrangi

Liang

et al. 2020

Preprint

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Background: Intracerebral hemorrhage (ICH) is the most devastating stroke subtype, with a poor prognosis and few proven treatments. Neuroinﬂammation is associated with ICH-induced brain injury and unfavorable outcomes. There is growing evidence that Dickkopf (DKK) 3 plays a key role in the adaptive anti-inflammatory and neuroprotective responses following intracerebral hemorrhage. This study aimed to evaluate the protective effects of DKK3 against brain edema and neuroinflammation in a mice model of ICH. Methods: Male, adult CD1 mice were subjected to sham or ICH surgery using a collagenase injection model. ICH animals received either recombinant DKK3, Kremen-1 siRNA, or DVL-1 siRNA. The neurobehavioral deficits were evaluated at 24 h, 72 h, and 28 days after ICH induction. Western blot and immunofluorescence were employed to examine the expression and localization of DKK3, Kremen-1, Dishevelled-1 (DVL-1), c-JUN N-terminal kinase (JNK), Activator protein-1 (AP-1), cleaved caspase-1, NF-κB, and IL-1β in the brain. Results: The expression of endogenous DKK3 and DVL-1 was transiently decreased after ICH compared to that in the sham group. Compared to the mice of ICH, exogenous rDKK3 administration reduced the brain water content and affected the neurological functions in ICH mice. Moreover, DKK3 was colocalized with Kremen-1 in microglia. Using a Kremen-1 or DVL-1 siRNA-induced in vivo knockdown approach, we demonstrated that the effects of DKK3 against ICH were mediated , at least partly, by the Kremen-1 and DVL-1 pathways. Conclusions: DKK3 improves the neurological outcomes, potentially by decreasing JNK/AP-1 mediated inflammation, thereby ameliorating the short- and long-term sequelae after ICH.

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A combined bioinformatics, experimental and clinical approach to identify novel cardiac‐specific heart failure biomarkers: is Dickkopf‐3 (DKK3) a possible candidate?

Piek

Suthahar

Voors

et al. 2020

European J of Heart Fail

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Aims Cardiac specificity provides an advantage in correlating heart failure (HF) biomarker plasma levels with indices of cardiac function and remodelling, as shown for natriuretic peptides. Using bioinformatics, we explored the cardiac specificity of secreted proteins and investigated in more detail the relationship of Dickkopf‐3 (DKK3) gene expression and DKK3 plasma concentrations with cardiac function and remodelling in (pre)clinical studies. Methods and results The cardiac specificity of secreted proteins was determined using RNAseq data for a large panel of organs and tissues. This showed that natriuretic peptides (NPPA and NPPB) are highly cardiac‐specific (>99%), whereas other HF biomarkers, including galectin‐3 (Gal‐3, LGALS3) and growth differentiation factor‐15 (GDF‐15), lack cardiac specificity (<4%). DKK3 was cardiac‐enriched (44%), warranting further investigation. In three different HF mouse models, cardiac Dkk3 expression was altered, but DKK3 plasma concentrations were not. In humans, DKK3 plasma concentrations were higher in HF patients (n = 2090) in comparison with age‐ and sex‐matched controls without HF (n = 240) (46.4 ng/mL vs. 36.3 ng/mL; P < 0.001). Multivariate regression analysis revealed that DKK3 was strongly associated with HF risk factors and comorbidities, including age, kidney function and atrial fibrillation. After correction for existing prediction models, DKK3 did not independently predict HF outcome [all‐cause mortality/HF hospitalization, hazard ratio 1.13 (0.79–1.61) per DKK3 doubling; P = 0.503]. Conclusions Of actively secreted HF biomarkers, only natriuretic peptides showed high cardiac specificity. Despite a cardiac specificity of 44%, secreted DKK3 had limited additional diagnostic and prognostic value.

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A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective

Abstract: Supplemental Digital Content is available in the text.

Cited by 56 publications

References 69 publications

Intracavernous delivery of Dickkopf3 gene or peptide rescues erectile function through enhanced cavernous angiogenesis in the diabetic mouse

Intracavernous delivery of Dickkopf3 gene or peptide rescues erectile function through enhanced cavernous angiogenesis in the diabetic mouse

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

A combined bioinformatics, experimental and clinical approach to identify novel cardiac‐specific heart failure biomarkers: is Dickkopf‐3 (DKK3) a possible candidate?

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