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The WNT antagonist Dickkopf2 promotes angiogenesis in rodent and human endothelial cells.
Min, Jeong-Ki,Park, Hongryeol,Choi, Hyun-Jung,Kim, Yonghak,Pyun, Bo-Jeong,Agrawal, Vijayendra,Song, Byeong-Wook,Jeon, Jongwook,Maeng, Yong-Sun,Rho, Seung-Sik,Shim, Sungbo,Chai, Jin-Ho,Koo, Bon-Kyoung American Society for Clinical Investigation 2011 The Journal of clinical investigation Vol.121 No.5
<P>Neovessel formation is a complex process governed by the orchestrated action of multiple factors that regulate EC specification and dynamics within a growing vascular tree. These factors have been widely exploited to develop therapies for angiogenesis-related diseases such as diabetic retinopathy and tumor growth and metastasis. WNT signaling has been implicated in the regulation and development of the vascular system, but the detailed mechanism of this process remains unclear. Here, we report that Dickkopf1 (DKK1) and Dickkopf2 (DKK2), originally known as WNT antagonists, play opposite functional roles in regulating angiogenesis. DKK2 induced during EC morphogenesis promoted angiogenesis in cultured human endothelial cells and in in vivo assays using mice. Its structural homolog, DKK1, suppressed angiogenesis and was repressed upon induction of morphogenesis. Importantly, local injection of DKK2 protein significantly improved tissue repair, with enhanced neovascularization in animal models of both hind limb ischemia and myocardial infarction. We further showed that DKK2 stimulated filopodial dynamics and angiogenic sprouting of ECs via a signaling cascade involving LRP6-mediated APC/Asef2/Cdc42 activation. Thus, our findings demonstrate the distinct functions of DKK1 and DKK2 in controlling angiogenesis and suggest that DKK2 may be a viable therapeutic target in the treatment of ischemic vascular diseases.</P>
Kang, Ga-Young,Pyun, Bo-Jeong,Seo, Haeng Ran,Jin, Yeung Bae,Lee, Hae-June,Lee, Yoon-Jin,Lee, Yun-Sil American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.45
<P>Our previous study suggested that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) interacts with Snail1, which affects genomic instability, sensitivity to DNA-damaging agents, and migration of tumor cells by reciprocal regulation between DNA-PKcs and Snail1. Here, we further investigate that a peptide containing 7-amino acid sequences (amino acids 15–21) of Snail1 (KPNYSEL, SP) inhibits the endogenous interaction between DNA-PKcs and Snail1 through primary interaction with DNA-PKcs. SP restored the inhibited DNA-PKcs repair activity and downstream pathways. On the other hand, DNA-PKcs-mediated phosphorylation of Snail1 was inhibited by SP, which resulted in decreased Snail1 stability and Snail1 functions. However, these phenomena were only shown in p53 wild-type cells, not in p53-defective cells. From these results, it is suggested that interfering with the protein interaction between DNA-PKcs and Snail1 might be an effective strategy for sensitizing cancer cells and inhibiting tumor migration, especially in both Snail1-overexpressing and DNA-PKcs-overexpressing cancer cells with functional p53.</P>
Kang, Nu Ri,Pyun, Bo-Jeong,Jung, Dong Ho,Lee, Ik Soo,Kim, Chan-Sik,Kim, Young Sook,Kim, Jin Sook Oxford University Press 2019 Evidence-based Complementary and Alternative Medic Vol.2019 No.-
<P> <I>Background.</I> Pueraria <I>lobata</I> is used in traditional Asian medicine to treat cardiovascular diseases, diarrhea, diabetes mellitus, and diabetic complications such as diabetic retinopathy. Oxidative stress in retinal pigment epithelial cells is implicated in the pathogenesis of retinopathy and age-related macular degeneration (AMD). Here, we evaluated whether the <I>P. lobata</I> extract can prevent cell death and decrease membrane permeability in oxidative stress-induced human retinal pigment epithelial cells. <I>Methods.</I> The effects of <I>P. lobata</I> extract on hydrogen peroxide- (H<SUB>2</SUB>O<SUB>2-</SUB>) induced oxidative stress were investigated using 2′,7′-dichlorofluorescin diacetate, western blotting, and immunohistochemistry in human retinal pigment epithelial cells. The effects of puerarin, daidzein, and daidzin isolated from <I>P. lobata</I> extract were also studied by determining cell death, reactive oxygen species (ROS) generation, and p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation. <I>Results.</I> Our results showed that the <I>P. lobata</I> extract inhibited ROS generation, suppressed the disruption of zonula occludens-1 (ZO-1), and reduced membrane permeability in H<SUB>2</SUB>O<SUB>2-</SUB>induced human retinal pigment epithelial cells. Additionally, the <I>P. lobata</I> extract prevented the inhibition of p38 MAPK and JNK phosphorylation. <I>Conclusion.</I> Our findings suggest that the <I>P. lobata</I> extract has the potential to prevent AMD development by inhibiting the mechanism underlying oxidative stress-mediated ocular disorders. </P>
Han, Na-Kyung,Jeong, Ye Ji,Pyun, Bo-Jeong,Lee, Yoon-Jin,Kim, Sung-Ho,Lee, Hae-June MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.10
<P>Radiation-induced intestinal toxicity is common among cancer patients after radiotherapy. Endothelial cell dysfunction is believed to be a critical contributor to radiation tissue injury in the intestine. Geranylgeranylacetone (GGA) has been used to treat peptic ulcers and gastritis. However, the protective capacity of GGA against radiation-induced intestinal injury has not been addressed. Therefore, we investigated whether GGA affects intestinal damage in mice and vascular endothelial cell damage in vitro. GGA treatment significantly ameliorated intestinal injury, as evident by intestinal crypt survival, villi length and the subsequently prolonged survival time of irradiated mice. In addition, intestinal microvessels were also significantly preserved in GGA-treated mice. To clarify the effect of GGA on endothelial cell survival, we examined endothelial function by evaluating cell proliferation, tube formation, wound healing, invasion and migration in the presence or absence of GGA after irradiation. Our findings showed that GGA plays a role in maintaining vascular cell function; however, it does not protect against radiation-induced vascular cell death. GGA promoted endothelial function during radiation injury by preventing the loss of VEGF/VEGFR1/eNOS signaling and by down-regulating TNFα expression in endothelial cells. This finding indicates the potential impact of GGA as a therapeutic agent in mitigating radiation-induced intestinal damage.</P>