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National Chung Hsing University Institutional Repository - NCHUIR > 獸醫學院 > 獸醫學系所 > 依資料類型分類 > 碩博士論文 >  蛛網膜下腔出血引起急性心臟損傷及誘發早期心肌基質金屬蛋白酶活化的研究

Please use this identifier to cite or link to this item: http://nchuir.lib.nchu.edu.tw/handle/309270000/155281

標題: 蛛網膜下腔出血引起急性心臟損傷及誘發早期心肌基質金屬蛋白酶活化的研究
Acute cardiac damage and early activation of myocardial matrix metalloproteinases after subarachnoid hemorrhage.
作者: 林乃女
Lin, Nai-Nu
Contributors: 何素鵬
Shu-Peng Ho
獸醫學系暨研究所
關鍵字: 蛛網膜下腔出血;急性心肌損傷;心室功能不全;心肌肌鈣蛋白 I;基質金屬蛋白酶老鼠動物模式
subarachnoid hemorrhage;acute myocardial damage;myocardial dysfunction;cardiac troponin I;matrix metalloproteinases;rats
日期: 2012
Issue Date: 2013-11-21 11:49:14 (UTC+8)
Publisher: 獸醫學系暨研究所
摘要: 臨床上,蛛網膜下腔出血(subarachnoid hemorrhage;SAH)的病人經常有急性心肌損傷及心室功能不全的現象。其致病原因最主要是因腦出血後,顱內壓升高導致交感神經過度興奮而來。這種交感神經風暴會促使心肌過度收縮而造成心肌損傷。但是,對於蛛網膜下腔出血引發心臟收縮功能不全的分子機轉研究則尚未有人提出。因此,建立一種簡單、穩定、可靠的動物模型,在蛛網膜下腔出血引起早期心肌損傷及心室功能障礙的病理生理機制研究上極為重要。肌鈣蛋白 I(cardiac troponin I;cTnI)已知是心肌細胞調控心臟收縮的一個重要結構蛋白,如果心肌中的肌鈣蛋白 I 被分解,則心臟的收縮會不完全而使心肌受損。基質金屬蛋白酶(matrix metalloproteinases;MMPs)在心肌細胞所扮演的角色不僅可以分解細胞外的細胞間質(extracellular matrix;ECM),亦可在很短的時間內(幾分鐘)分解細胞內的肌鈣蛋白 I,致使心臟收縮不完全。因此本實驗則提出蜘蛛膜下腔出血後,基質金屬蛋白酶可在心肌組織中被活化而增加心肌肌鈣蛋白 I 的分解,導致急性心臟收縮功能不全。我們利用 3/0 nylon 線穿刺大白鼠大腦動脈,模擬蛛網膜下腔出血。在出血後極短時間內(0-180分鐘)有類似臨床常見顱內壓、平均動脈壓及心跳顯著性的升高,並伴隨著心律的異常、左心室舒張功能指數(−LV dP/dtmax)的下降以及交感神經傳遞物正腎上腺素的上升。180分鐘後以肉眼觀察心室有明顯擴張、塌陷及鬱血的現象,並有類似蛛網膜下腔出血病患心肌 myocytolysis 和橫紋消失的病理病變產生。由血液肌鈣蛋白 I 濃度的上升及心肌肌鈣蛋白 I 免疫組織化學染色的流失,可進一步診斷為早期心肌損傷。因此,本動物模式可作為模擬人類蛛網膜下腔出血誘發急性心臟損傷及心肌功能障礙的實驗模式。接著進行導致心臟收縮功能不全之分子機轉研究。首先研究心臟受損後血液及心肌基質金屬蛋白酶(MMP-2,MMP-9)表現量的變化,以及基質金屬蛋白酶對於負責調節心肌收縮的心肌肌鈣蛋白 I 裂解作用的影響。出血後左心室功能明顯下降,血液中 pro-MMP-9 及肌鈣蛋白 I 濃度明顯上升。心肌內很快的(甚至於提早至30分鐘)activated MMP-2、pro-MMP-2 及 pro-MMP-9 活性增強,伴隨著心肌肌鈣蛋白 I 完整性的降低及裂解比例的增高。在相關性的分析上,心肌基質金屬蛋白酶活性的增強、心肌肌鈣蛋白 I 蛋白含量的減少與心室舒張能力的維持有密切的關係。這些結果顯示早期蛛網膜下腔出血可誘發活化基質金屬蛋白酶及水解心肌肌鈣蛋白 I,而導致心室功能不全。因此,本實驗結果可作為臨床上蛛網膜下腔出血引發早期心臟損傷與心功能不全預防和治療之方針。
Early cardiac damage and reversible ventricular dysfunction (stunning) have been reported in humans with subarachnoid hemorrhage (SAH). It has been considered that sympathetic activity with catecholamine-mediated injury is the most likely cause of cardiac injury after SAH. However, the molecular pathogenesis of ventricular dysfunction in SAH hemorrhage remains unknown. Investigations of early cardiac damage and ventricular dysfunction occurring immediately after SAH are important, but would be impossible to conduct without a good animal model. Cardiac troponin I (cTnI) is a key regulatory protein in cardiac muscle contraction and relaxation. Selective proteolysis of cTnI has recently been proposed to play a key role in the contractile dysfunction observed in stunned myocardium. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases which are synthesized as zymogens. MMPs not only extracellularly remodel the ECM but also act intracellularly in contractile dysfunction hearts by degrading troponin I. Therefore, we wish to test the hypothesis that activation of MMPs (MMP-2 or/and MMP-9) and subsequent cleavage of troponin I in ventricular may cause acute myocardial damage and contractile dysfunction after SAH. SAH was induced by the endovascular suture method in rats. SAH induced increases in mean blood pressure, heart rate, intracranial pressure and plasma norepinephrine accompanied with electrocardiogram abnormalities and ventricular dysfunction. The heart was dilated. Myocardial damage was evident from the increased plasma cTnI and marked loss of myocardial tissue cTnI in myocytolytic areas at 180 minutes after SAH. Thus, we create a rat SAH model that can be applied in studying mechanisms of the early myocardial damage and ventricular dysfunction following SAH and for evaluating therapeutic strategies in SAH patients. To study the molecular mechanisms leading to contractile dysfunction in the acute stage of SAH, we examined the temporal profiles of MMPs and cTnI in blood and heart tissue and to determine whether changes in these profiles are associated with myocardial dysfunction and cTnI degradation. Following SAH, there was an early increase (as early as 30 minutes) in activated MMP-2 expression, pro-MMP-2 and pro-MMP-9 activities in myocardium that was accompanied by a decrease in tissue cTnI integrity. The enhanced myocardial MMP-2 and -9 activities and the loss of tissue cTnI content correlated with the –LV dP/dtmax (index of left ventricular diastolic function). The degradation of tissue cTnI and the release of plasma cTnI were also increased following SAH. These data showed that SAH could induce the activation of MMPs and proteolysis of cTnI that lead to cardiac dysfunction.
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