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標題: 缺氧蛋白BNIP3及鈣離子誘導蛋白E4BP4對心肌細胞傷害及保護之調控機轉探討
Regulatory mechanisms of BNIP3 and E4BP4 in cell death and protection of cardiomyocytes
作者: 翁宜君
Weng, Yi-Jiun
關鍵字: BNIP3
出版社: 獸醫學系暨研究所
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摘要: 缺氧誘導標的蛋白BNIP3及生存相關蛋白E4BP4皆在疾病心臟中會大量增加。本研究將個別針對BNIP3及E4BP4探討其在心臟中的角色和調控機制。近期的報告指出,抑制BNIP3可以遏止心肌細胞的凋亡及梗塞後的心臟重組反應。因此,研究BNIP3是一個重要的治療標的,然而,BNIP3是否誘導肥大反應現今並沒有直接的報告與研究。在此研究中,我們將H9c2心肌原母細胞株短暫轉殖入並過量表現BNIP3,去偵測肥大訊息與現象是否發生,並利用細胞骨架染色來測量細胞大小。發現BNIP3過量表現會使得心肌細胞肥大,同時也使得病理性肥大的訊息路徑都被活化,包括: IL6-MEK5-ERK5, IL6-JAK2-STAT1/3, calcineurin/NFAT3以及p38β MAPK。除此之外,也促使了肥大的標的基因: ANP及BNP的蛋白量增加。總結以上的結果, BNIP3會誘導病理性肥大的發生,在未來可幫助新藥開發及當作治療的目標。雌性素及雌性素接受體-α (E2/ERα)皆可對抗粒線體依賴型凋亡路徑的發生,對心臟缺血缺氧傷害確實具有保護作用。進一步研究E2/ERα對BNIP3所誘導的自噬與凋亡反應之調控機制。在MTT及西方點墨法實驗中,利用capase-3抑制劑來抑制凋亡發現自噬作用會增強,而加入rapamycin來促進自噬時更促進BNIP3所造成的細胞死亡。經由TUNEL實驗觀察凋亡小體的減少及西方點墨法觀察caspase-3, Atg5及LC3-II皆有被ERα抑制的效果,得知E2/ERα對BNIP3造成的凋亡與自噬反應皆具有抑制之效果。經免疫沉澱實驗發現,ERα與BNIP3的結合反應強制的減少了BNIP3與其他蛋白Bcl-2及Rheb的結合。這表示ERα抑制了BNIP3去誘導凋亡及自噬反應的發生。此外,透過螢光酵素報告基因實驗發現,ERα可能會經由SP-1或NFkB對BNIP3的基因進行壓制的調控。由實驗結果推測ERα可以經由抑制BNIP3的基因轉錄及蛋白結合作用來抑制BNIP3所誘導的自噬與凋亡反應進而保護心臟。在另一主題,E4BP4屬於bZIP轉錄因子之ㄧ員,文獻證實E4BP4在造血細胞株中是一生存因子。然而,E4BP4在心臟中扮演的角色仍屬未知。我們利用Dot-blot技術及西方點墨法偵測各種哺乳動物心臟,發現確實有E4BP4的表現。而以免疫化學染色觀察,在人類疾病心臟組織中也看到E4BP4表現量的增加,並且當我們在新生鼠初代培養心肌細胞中將E4BP4過量表現則活化了促進生存訊息路徑蛋白如:IGF-1/IGF-1R、Bcl-2及p-Akt的表現進而來保護心臟。因此我們認為E4BP4在心臟中亦是生存因子。在先天性高血壓鼠(SHR)的心臟中也發現了E4BP4表現量增加,進一步我們探討E4BP4對血管昇壓素(AngII)造成心肌細胞凋亡之反應。由TUNEL及DNA斷裂的實驗觀察E4BP4減弱AngII所造成心肌細胞凋亡的情形。由mRNA及蛋白質層次觀察,E4BP4會經由PI3K-Akt的訊息路徑來減弱AngII所誘導的IGF-II表現及caspase-3的活化。並且,E4BP4更會去減少活化態PP2A、促進PKA及PLB的活化,進而促使鈣離子回收進入SR儲存。因此也抑制了Ang-II誘導的calcineurin的活化。此研究不但最新定義了E4BP4在心臟中屬生存因子,並可經由活化PI3K-Akt路徑及調控細胞內鈣離子濃度進而抑制Ang-II所誘導的凋亡反應。相信此研究之成果將對於心肌傷害之治療,臨床用藥及促進人體之健康有極其重要的意義。
Hypoxia-inducible marker, BNIP3, and survival-related E4BP4 are both upregulated in disease hearts. In this study, we focused on BNIP3 and E4BP4 respectively, to explore their roles and regulatory mechanisms in heart. Recent reports discussed ablating BNIP3 can restrain cardiomyocytes apoptosis and post-infarction remodeling. BNIP3 is a crucial therapeutic target. However, the BNIP3-induced hypertrophy aspect is rarely investigated. Here, we transiently transfected BNIP3 plasmids into H9c2 cardiomyoblast cells to evaluate the molecular signaling and hypertrophy markers using Western blot, and measure the cell size change using actin staining. We disclose that BNIP3 overexpression induced an increase in cell size, activated the pathological-related hypertrophy signaling pathways, such as IL6-MEK5-ERK5, IL6-JAK2-STAT1/3, calcineurin/NFAT3 and p38β MAPK resulting in the fetal genes, ANP and BNP expressing. Concluding above, BNIP3 acts as a pathological hypertrophy inducer, which might be a potential therapeutic target for heart damage prevention. ERα/E2 exert cardiac protection to against mitochondria-dependent apoptosis in I/R injury heart. We further uncover the regulatory mechanism of ERα on BNIP3-depedent effect. Autophagy was evidenced as an alternative death pathway when apoptosis was blocked by caspase-3 inhibitor (Z-DEVD-FMK) in BNIP3-overexpressed cells. Improving autophagy by rapamycin administration further enlarged the death effect of BNIP3-overexpressed cells evidenced by MTT cell viability and Western blot. ERα/E2 reduced BNIP3-induced apoptosis and autophagy by decrease the apoptotic cells in TUNEL assay and by decrease the protein levels of caspase 3, Atg5, LC3-II. By assay coimmunoprecipitation of BNIP3 and immunoblot of Bcl-2 and Rheb, we showed that the binding effect between ERα and BNIP3 reduced the interaction of BNIP3 with Bcl-2 or Rheb. It suggests the strong binding effect of ERα and BNIP3 inhibit the initiations of apoptosis and autophagy. In addition, ERα could repress BNIP3 promoter activity via binding to SP-1 or NFkB site. We speculate that ERα exerts the protective effect through repressing BNIP3 expression and strong binding with BNIP3 to retrain the BNIP3-induced autophagy and apoptosis effects. On the other hands, the bZIP transcription factor E4BP4, has been demonstrated to be a survival factor in pro-B lymphocytes. However, the role E4BP4 playing in heart is still poorly understood. Dot-blot hybridization assays using Dig-labled RNA probes revealed that the E4BP4 gene was expressed in cardiac tissue from several species including, monkey, dog, rabbit, and human. Western blot analysis showed that the E4BP4 protein was consistently present in all of these four species. Furthermore, immunohistochemistry revealed that the E4BP4 protein was overexpressed in diseased heart tissue in comparison with normal heart tissue. In addition, the overexpression of E4BP4 in vitro activated cell survival signaling pathway, including IGF-1/IGF-1R, Bcl-2, and p-Akt to rescue cardiomyocytes from apoptosis. Based on these results, we conclude that E4BP4 plays as a survival factor in heart. Previous study showed that E4BP4 expression was raised in hearts of spontaneously hypertensive rats (SHR). We tested the effect of E4BP4 on AngII-induced cardiomyocyte apoptosis. TUNEL and DNA fragmentation assays revealed that E4BP4 attenuated the apoptosis induced by AngII in H9c2 cardiomyoblast cells. Western blot and RT-PCR analysis showed that E4BP4 repressed the AngII-induced IGF-II mRNA expression and caspase-3 cleavage through PI3K-Akt pathway. Additionally, E4BP4 improved calcium reuptake into SR via down-regulating PP2A, up-regulating phosphorylated PKA and phosphorylated PLB, since inactive the AngII-induced calcineurin activation. This is a novel discovery that E4BP4 exerted as a survival factor in cardiomyoblasts and inhibited the AngII-induced apoptotic effect through blocking IGF-II transcription and regulating calcium cycling.
其他識別: U0005-2101201120244200
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