https://scholars.lib.ntu.edu.tw/handle/123456789/188406
標題: | 過氧化體增殖劑活化受器促進劑Rosiglitzaone對於大白鼠過度左心室後負荷所致心衰竭的心肌整體基因表現型態之影響 | 其他標題: | Global gene expression profiling of congestive heart failure subsequent to experimental left ventricular pressure overload pretreated with the peroxisome proliferator-activated receptor-gama agonist Rosiglitazone | 作者: | 黃瑞仁 | 關鍵字: | 過氧化體增殖劑活化受器促進劑;過度壓力負荷;心臟衰竭;cDNA 微陣列技術;整體基因表現型態;peroxisome proliferator-activated receptor-g agonist;pressure overload;congestive heart failure;remodeling;cDNA microarray;gene expression profiling | 公開日期: | 2005 | 出版社: | 臺北市:國立臺灣大學醫學院內科 | 摘要: | 高血壓一直為公衛上一個相當重要的議題。?所周知,高血壓是許多神經系統以及 心血管系統的併發症的一個重要的危險因子。好好控制高血壓可以有效增進患者的預 後。然而根據研究指出,仍然有三分之一的患者,其掏血壓仍無法被控制在滿意的範圍 之內。長期未良好控制的高血壓將會使左心室的心室後負荷上升,心肌細胞為了維持心 輸出量,心肌細胞會變的肥厚來應付所需的功,於是乎左心室肥厚便產生。而同時,纖 維母細胞也會被活化,使的collagen 產量增加,而使的間質增生亦隨之增加,並開始 產生心肌細胞之纖維化。早期只是單純的心室肥厚,因此雖有心臟舒張功能失調,但是 心肌之收縮功能正常;而到晚期,心臟的收縮功能亦會受到影響,而進展到代償不良之 心臟衰竭。心肌梗塞後,細胞骨架和收縮元件的變化,與Actin 和myosin 基因表現改 變相關,而Collagen 和fibronectin 基因表現則是梗塞組織纖維化的部份原因。梗塞 後,為了改善血行動力,心肌組織中atrial natriuretic peptide mRNA 及其蛋白質產 物也會增加;而內皮一氧化氮生成?(eNOS),細胞外間質(ECM)metalloproteinases (MMPs)和腫瘤壞死因子(TNF)的基因表現亦牽涉其中,同時存活的心肌組織也會變的更 為肥厚。這些變化皆與心肌梗塞後心臟進行再塑型(remodeling)作用息息相關,也對梗 塞造成之心臟衰竭演進有相當之影響。 過氧化體增殖劑活化受器(PPARs)屬細胞核內受器群,共分三種亞型a 、b /d 、和g , 其為轉譯因子,可調節基因表現並控制不同方面的細胞功能,包含脂肪和脂蛋白的代 謝,脂肪酸氧化,葡萄糖代謝,脂肪新生,細胞分化等等。近來研究亦發現PPARs 表現 也會影響免疫細胞、巨嗜細胞、內皮細胞和血管平滑肌細胞,並影響不同細胞之細胞激 素(cytokines)分泌或其他酵素分泌(如MMPs),因此對血管硬化之調控亦有重要角色。 PPAR g 促進劑在動物模式顯示可減少心肌梗塞區域及收縮功能失常,且對於梗塞後左心 室再塑型作用及心臟衰竭也具有減緩之作用。不僅如此,對於心肌肥厚的進展,PPAR g 也在不同研究中顯示有減緩之作用。唯目前僅知道與部分細胞產物有關,對於長期左心 室壓力過度負荷後心肌整體影響以及保護機轉明瞭則相當少。 cDNA 微陣列晶片(cDNA microarray)可以同時分析成千的基因表現,對疾病致病機轉研 究助益甚大。本研究希望藉此有效的研究平台來深入解析PPAR g 促進劑Rosiglitazone 對 心肌梗塞可能具保護作用的機轉以及其影響梗塞後心衰竭演進的機制,並希望應用到日 後心肌梗塞之治療。 Aim of study: To explore the gene expression profiles of congestive heart failure (CHF) subsequent to experimental pressure overload pretreated with peroxisome proliferator-activated receptor-g (PPARg) agonist Rosiglitazone. And to elucidate the potential benefits and mechanisms of PPARg agonist on pressure-overload hemodynamics, cardiac remodeling, and CHF. Background: Hypertension (HTN) continues to be of major public health concern. Increased risks of several adverse neurological and cardiovascular outcomes were documented in the population of HTN. Longstanding HTN increased the left ventricular (LV) afterload markedly, and cardiac fibrosis evolves as an adaptive response to hemodyanamic overload. Subsequently, interstitial fibrosis occurred and contributed to LV stiffening and impaired compliance. Although initially the LV systolic function is well preserved with simply diastolic dysfunction, however progression to decompenated stage congestive heart failure (CHF) with systolic dysfunction is hastened. PPARs are nuclear receptors, which function as transcription factors the regulate different genes expression. They control a variety of cellular functions and are involved in control of vascular inflammation, thrombogenecity and inflammatory cytokines. Several animal studies had shown that ligands of the PPARs can reduce infarct size and potentially protect the heart against ischemia-reperfusion injury. PPARg ligands have also been shown to suppress the development of cardiac myocyte hypertrophy both in vitro and in the in vivo setting. However, knowledge about the influences of PPARs on pressure-loaded CHF and cardiac remodeling process at cellular level is quite limited. cDNA microarray offers a genome-wide simultaneous analysis of gene expression profiling changes in perturbed physiological or pathological conditions. With the aid of this powerful tool, researches could progress efficiently. Experimental protocol: Rosiglitazone-pretreated or placebo-preteated rats undergo abdominal aorta ligation resulting in left ventricular overload. Two-color cDNA microarray system containing 7,600 clones from regional company is applied to explore the cardiac differential gene expressions between Rosiglitzaone-pretreated and placebo-pretreated rat pressure overload model. Serum biochemistry, hemodynamics, echocardiography, and clinical conditions are also measured prior to sacrifice and will be analyzed. Expected results: The two-color cDNA microarray data analysis will be validated utilizing RT-PCR. Through this study, Rosigliazone pretreatment effects, whether beneficial or not, on pressure overload cardiac remodeling and CHF course could be evaluated, and differential cardiac gene expressions contributing to the probable beneficial effect of Rosiglitazone on CHF subsequent to pressure overload could be elucidated. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/23711 | 其他識別: | 932314B002224 | Rights: | 國立臺灣大學醫學院內科 |
顯示於: | 醫學系 |
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