中國醫藥大學機構典藏 China Medical University Repository, Taiwan:Item 310903500/58523
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    Title: 丹參酮 IIA透過抑制β-Catenin核轉位和活化胰島素生長因子II受器調節雌激素受體信號傳遞來保護血管張力素誘導的心臟損傷
    Tanshinone IIA modulated estrogen receptor signaling protects against Angiotensin II-induced cardiac damages by inhibiting β-Catenin Nuclear Translocation and IGF-2R Activation
    Authors: 陳雅芳;Yang-Fan Chen
    Contributors: 基礎醫學研究所博士班
    Keywords: 丹參酮 IIA;活化胰島素生長因子II受器;雌激素受體;血管張力素;Angiotensin II;β-catenin;estrogen receptors;H9c2 cardiomyoblasts;IGF-2R;tanshinone IIA
    Date: 2018-07-06
    Issue Date: 2018-12-25 10:08:49 (UTC+8)
    Publisher: 中國醫藥大學
    Abstract: 心肌病變和心肌結構上的改變及心臟肥大有關。血管加壓素II(angiotensin II (AngII))在之前的報到中發現在H9c2心肌原母細胞中可刺激類胰島生長激素II (insulin growth factor 2 (IGFII))及IGF-2接受器(IGF-2R)之表現及接下來的血壓上升和心臟肥大。雌激素接受器(estrogen receptors (ERs))對心肌細胞具有保護作用。丹參酮 IIA (tanshinone IIA)是一個從丹參中發現之一個主成分，被發現保護心肌細胞免於因不同之刺激因子造成之凋亡。本研究之目的在於探討丹參是否透過ERs以抑制AngII在H9c2心肌原母細胞中造成之β-catenin及IGF-2R訊息傳遞路徑和細胞傷害。AngII在H9c2心肌原母細胞中造成肥大及使發炎蛋白表現增加。但是，TSN透過ERs減少了這些現象。AngII造成了MAPKs、IGF-2R和肥大蛋白明顯上升。這些現象也是被TSN透過ERs所減少。最後，AngII引發了heat shock factor 1 (HSF1)之磷酸化、使SIRT1減少及細胞膜上之IGF-2R分子分佈增加。相反地，TSN透過了ERs減少HSF1磷酸化和細胞膜上IGF-2R並且使SIRT1表現上升。所以，TSN能夠在H9c2心肌原母細胞中透過ERs以抑制AngII所誘導之IGF-2R訊息傳遞路徑及肥大。

    心肌病變和心肌結構上的改變、心臟肥大、凋亡、纖維化及發炎有關。血管加壓素II (angiotensin II (AngII))在H9c2心肌原母細胞中可刺激類胰島生長激素II (insulin growth factor 2 (IGFII))之表現及之後的凋亡。雌激素接受器 (estrogen receptors (ERs))保護心肌細胞免於凋亡及纖維化。丹參酮 IIA (tanshinone IIA)是一個從丹參中發現之一個主成分，被發現保護心肌細胞免於因不同之刺激因子造成之凋亡。本研究之目的在於探討丹參是否透過ERs以抑制AngII在H9c2心肌原母細胞中引發之β-catenin及IGF-2R訊息傳遞路徑、凋亡和纖維化。AngII造常成了IGF-1R磷酸化之減少及β-catenin和IGF-2R上升。TSN則隨著劑量增加透過了ERs逆轉了此一現象並且減少了caspase-3和ERK1/2磷酸化。然後，TSN顯著地抑制了AngII引發之凋亡及纖維化。所以，tanshinone IIA能夠在H9c2心肌原母細胞中透過ERs以減低AngII引發之β-catenin和IGF-2R訊息傳遞路徑、凋亡及纖維化。
    Cardiomyopathy involves changes in myocardial ultrastructure and cardiac hypertrophy. Angiotensin II (AngII) has previously been shown to stimulate the expression of IGF-2 and IGF-2R in H9c2 cardiomyoblasts and increase of blood pressure, and cardiac hypertrophy. Estrogen receptors (ERs) exert protective effects, such as anti-hypertrophy in cadiomyocytes. Tanshinone IIA (TSN), a main active ingredient from a Chinese medical herb, Salvia miltiorrhiza Bunge (Danshen), was shown to protect cardiomyocytes hypertrophy by different stress signals. We aimed to investigate whether TSN protected H9c2 cardiomyocytes from AngII-induced activation of IGF-2R pathway and hypertrophy by mediating through ERs. AngII resulted in H9c2 cardiomyoblast hypertrophy and increased inflammatory molecular markers. These were down-regulated by TSN via estrogen receptors. AngII resulted in elevation in MAPKs, IGF-2R and hypertrophic protein markers. These, again, were reduced by addition of the phytoestrogen with activation of ERs. Finally, AngII induced phosphorylation of heat shock factor-1 (HSF1) and decreased sirtuin-1 (SIRT1). In addition, AngII also caused an increase in distribution of IGF-2R molecules on cell membrane. In contrast, TSN reduced HSF1 phosphorylation and cell surface IGF-2R while elevating SIRT1 via ERs. TSN was capable of attenuating AngII-induced IGF-2R pathway and hypertrophy through ERs in H9c2 cardiomyoblast cells.

    Cardiomyopathy involves changes in myocardial ultrastructure and cardiac hypertrophy. Angiotensin II (AngII) has previously been shown to stimulate the expression of IGF-2 and IGF-2R in H9c2 cardiomyoblasts and increase of blood pressure, and cardiac hypertrophy. Estrogen receptors (ERs) exert protective effects, such as anti-hypertrophy in cadiomyocytes. Tanshinone IIA (TSN), a main active ingredient from a Chinese medical herb, Salvia miltiorrhiza Bunge (Danshen), was shown to protect cardiomyocytes hypertrophy by different stress signals. We aimed to investigate whether TSN protected H9c2 cardiomyocytes from AngII-induced activation of IGF-2R pathway and hypertrophy by mediating through ERs. AngII resulted in H9c2 cardiomyoblast hypertrophy and increased inflammatory molecular markers. These were down-regulated by TSN via estrogen receptors. AngII resulted in elevation in MAPKs, IGF-2R and hypertrophic protein markers. These, again, were reduced by addition of the phytoestrogen with activation of ERs. Finally, AngII induced phosphorylation of heat shock factor-1 (HSF1) and decreased sirtuin-1 (SIRT1). In addition, AngII also caused an increase in distribution of IGF-2R molecules on cell membrane. In contrast, TSN reduced HSF1 phosphorylation and cell surface IGF-2R while elevating SIRT1 via ERs. TSN was capable of attenuating AngII-induced IGF-2R pathway and hypertrophy through ERs in H9c2 cardiomyoblast cells.Key words: Angiotensin II; β-Catenin; Estrogen receptors; H9c2 Cardiomyoblasts; Insulin-like Growth Factor-2 Receptor; Tanshinone IIA.
    Appears in Collections:[Graduate Institute of Basic Medical Science] Theses & dissertations

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