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RISS 인기검색어
- 검색키워드
- 저자 : Hajjar Roger J. (검색결과 2 건)
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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>
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Sakata, Susumu,Liang, Lifan,Sakata, Naoya,Sakata, Yuri,Chemaly, Elie R,Lebeche, Djamel,Takewa, Yoshiaki,Chen, Jiqiu,Park, Woo Jin,Kawase, Yoshiaki,Hajjar, Roger J Blackwell Publishing Asia 2007 Clinical and experimental pharmacology & physiolog Vol.34 No.12
<P>SUMMARY</P><OL TYPE='1'><li level='1'>The aim of the present study was to examine the acute and chronic effects of adenoviral gene transfer on cardiac function in terms of left ventricular (LV) mechanoenergetic function. Recombinant adenoviral vector carrying &bgr;-galactosidase and green fluorescent protein genes (Ad.&bgr;gal-GFP) was used. Cardiac function was examined in cross-circulated rat heart preparations, where end-systolic/diastolic pressure–volume relationships (ESPVR/EDPVR), systolic pressure–volume area (PVA), LV relaxation rate, equivalent maximal elastance at mid-range LV volume (eE<SUB>max</SUB> at mLVV), coronary blood flow, coronary vascular resistance and myocardial oxygen consumption (VO<SUB>2</SUB>) were also measured.</LI><li level='1'>To examine the <I>ex vivo</I> acute effects of the adenoviral vector, data were obtained before and 30–90 min after intracoronary infusion of Ad.&bgr;gal-GFP in the excised, cross-circulated hearts that underwent serotonin pretreatment. To examine the <I>in vivo </I>chronic effects of adenoviral gene transfer, normal rat hearts received Ad.&bgr;gal-GFP or saline by a catheter-based technique and data were obtained 3 days after the injection of Ad.&bgr;gal-GFP or saline.</LI><li level='1'>The ESPVR, EDPVR, LV relaxation rate, eE<SUB>max</SUB> at mLVV, coronary blood flow and coronary vascular resistance remained unchanged in Ad.&bgr;gal-GFP-transfected hearts in both <I>ex vivo</I> acute and <I>in vivo </I>chronic experiments. Moreover, the <I>ex vivo</I> and <I>in vivo </I>transfection caused no change in the slope and VO<SUB>2</SUB> intercept of the VO<SUB>2</SUB>–PVA relationship, VO<SUB>2</SUB> for basal metabolism and for Ca<SUP>2+</SUP> handling in excitation–contraction coupling and O<SUB>2</SUB> costs of LV contractility.</LI><li level='1'>These results indicate that adenoviral gene transfer has neither acute nor chronic toxic effects on LV mechanical and energetic function. A special combination of <I>in vivo </I>adenoviral gene transfer and a cross-circulation experimental system may provide a useful novel strategy to explore the functional and mechanoenergetic role of specifically targeted genes in the diseased heart.</LI></OL>
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