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Yoonhee Bae,Jell Lee,Changwon Kho,Joon Sig Choi,Jin Han 대한생리학회-대한약리학회 2021 The Korean Journal of Physiology & Pharmacology Vol.25 No.5
In this study, we aimed to synthesize PAMAMG3 derivatives (PAMAMG3- KRRR and PAMAMG3-HKRRR), using KRRR peptides as a nuclear localization signal and introduced histidine residues into the KRRR-grafted PAMAMG3 for delivering a therapeutic, carcinoma cell-selective apoptosis gene, apoptin into human primary glioma (GBL-14) cells and human dermal fibroblasts. We examined their cytotoxicity and gene expression using luciferase activity and enhanced green fluorescent protein PAMAMG3 derivatives in both cell lines. We treated cells with PAMAMG3 derivative/ apoptin complexes and investigated their intracellular distribution using confocal microscopy. The PAMAMG3-KRRR and PAMAMG3-HKRRR dendrimers were found to escape from endolysosomes into the cytosol. The JC-1 assay, glutathione levels, and Annexin V staining results showed that apoptin triggered cell death in GBL-14 cells. Overall, these findings indicated that the PAMAMG3-HKRRR/apoptin complex is a potential candidate for an effective nonviral gene delivery system for brain tumor therapy in vitro.
Matricellular Protein CCN5 Reverses Established Cardiac Fibrosis
Jeong, Dongtak,Lee, Min-Ah,Li, Yan,Yang, Dong Kwon,Kho, Changwon,Oh, Jae Gyun,Hong, Gyeongdeok,Lee, Ahyoung,Song, Min Ho,LaRocca, Thomas J.,Chen, Jiqiu,Liang, Lifan,Mitsuyama, Shinichi,D'Escamard, Val American College of Cardiology 2016 Journal of the American College of Cardiology Vol.67 No.13
<P><B>Abstract</B></P><P><B>Background</B></P><P>Cardiac fibrosis (CF) is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with heart failure (HF). We previously showed that the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF and preserve cardiac contractility.</P><P><B>Objectives</B></P><P>This study examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload.</P><P><B>Methods</B></P><P>Human hearts were obtained from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined.</P><P><B>Results</B></P><P>Expression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NFκB, an antiapoptotic molecule.</P><P><B>Conclusions</B></P><P>CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies.</P>
Role of the PRC2-Six1-miR-25 signaling axis in heart failure
Oh, Jae Gyun,Jang, Seung Pil,Yoo, Jimeen,Lee, Min-Ah,Lee, Seung Hee,Lim, Taejoong,Jeong, Eden,Kho, Changwon,Kook, Hyun,Hajjar, Roger J.,Park, Woo Jin,Jeong, Dongtak Elsevier 2019 Journal of molecular and cellular cardiology Vol.129 No.-
<P><B>Abstract</B></P> <P>The reduced expression of cardiac sarco-endoplasmic reticulum Ca<SUP>2+</SUP> ATPase (SERCA2a) is a hallmark of heart failure. We previously showed that miR-25 is a crucial transcriptional regulator of SERCA2a in the heart. However, the precise mechanism of cardiac miR-25 regulation is largely unknown. Literatures suggested that miR-25 is regulated by the transcriptional co-factor, sine oculis homeobox homolog 1 (Six1), which in turn is epigenetically regulated by polycomb repressive complex 2 (PRC 2) in cardiac progenitor cells. Therefore, we aimed to investigate whether Six1 and PRC2 are indeed involved in the regulation of the miR-25 level in the setting of heart failure. Six1 was up-regulated in the failing hearts of humans and mice. Overexpression of Six1 led to adverse cardiac remodeling, whereas knock-down of Six1 attenuated pressure overload-induced cardiac dysfunction. The adverse effects of Six1 were ameliorated by knock-down of miR-25. The epigenetic repression on the <I>Six1</I> promoter by PRC2 was significantly reduced in failing hearts. Epigenetic repression of Six1 is relieved through a reduction of PRC2 activity in heart failure. Six1 up-regulates miR-25, which is followed by reduction of cardiac SERCA2a expression. Collectively, these data showed that the PRC2-Six1-miR-25 signaling axis is involved in heart failure. Our finding introduces new insight into potential treatments of heart failure.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Six1 is up-regulated in failing hearts. </LI> <LI> Overexpression of Six1 leads to cardiac abnormalities in vitro and in vivo. </LI> <LI> In cardiac stress conditions, Six1 directly binds to the <I>MCM7</I> promoter, inducing an elevation of miR-25, which in turn reduces SERCA2a. </LI> <LI> In failing hearts, Six1 is epigenetically regulated through the PRC2 complex across species. </LI> </UL> </P>