- 學位論文
探討斑馬魚心臟再生過程中L型鈣離子通道對於心電圖異常與電生理重整的影響
The Role of L-type Calcium Channel in ECG Abnormalities and Electrical Remodeling during Zebrafish Heart Regeneration
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摘要
心肌梗塞是心血管疾病中的代表疾病，於冠狀動脈受到阻塞時發生。此時心臟的循環會受到阻礙，並使血液無法充分供給到心肌細胞，進而造成心肌缺氧，甚至可能導致心肌細胞的死亡。在成熟的哺乳類動物中，心肌梗塞所導致受傷組織區域會形成一個不具有收縮功能且無法回復的纖維化組織。而和人類的心臟再生能力不同，斑馬魚在心室受到嚴重的損傷後仍然可以恢復心臟的功能。因此，許多研究都致力於探討斑馬魚的心臟再生機制，以期幫助人類的心臟修復。 在心臟的損傷反應中，鈣離子的調節會影響心臟的收縮以及電興奮性。CACNA1C是一種高度保守的基因，能夠在人類及斑馬魚中轉譯生成L型鈣離子通道的α1C亞基。已知CACNA1C的基因缺陷會造成各種不同的心律不整症狀，例如長QT症候群、短QT症候群、Brugada症候群以及早期再極化症狀。先前的研究也有發現CACNA1C的突變和心臟肥大與纖維化的形成有關。因此，我們認為L型鈣離子通道可能是斑馬魚心室創傷後，於心臟再生過程中減緩心電圖異常發生的關鍵因素。 為了驗證這個假設，在這項研究中我們首先進行了斑馬魚心臟再生過程中cacna1c的基因表達分析，並發現cacna1c斑馬魚心臟創傷後的第7天表達量會明顯下降，再於第21天時上升。接下來我們注射L型鈣離子通道的拮抗劑與促效劑到斑馬魚體內，藉以觀察鈣離子通道的活性改變是否會影響斑馬魚心臟再生過程中的電生理活動。最後，我們的心電圖分析釐清QT間期、PR間期，QRS波群，病理性Q波和ST節段上升的變化，並且辨識哪幾個心電圖特徵可作為斑馬魚心臟再生過程中電生理活動的分析參數，有助於判斷斑馬魚的心臟功能恢復或惡化進程。上述的發現能夠幫助理解斑馬魚心臟再生過程中，L型鈣離子通道的功能與電生理重整之間的關係，並且揭露鈣離子的訊號傳遞路徑和鈣離子的恆定，可能在調節斑馬魚心臟再生過程中的心臟修復中有著重要作用。
並列摘要
As a representative disorder of cardiovascular diseases, myocardial infarction occurs when the cardiac circulation is disrupted and the subsequent shortage of oxygen supply results in cell death of cardiomyocytes. In adult mammals, the infarction region will transform into an irreversible fibrotic tissue with sequelae of contractile dysfunction. In contrast, zebrafish can regenerate severe ventricular damage and restore cardiac functions. Such finding has impelled numerous studies to scrutinize zebrafish heart regeneration in hopes of unlocking the regenerative potential in human. In cardiac injury responses, regulation of calcium flux affects the cardiac contractility and excitability. CACNA1C (Calcium Voltage-Gated Channel Subunit Alpha1 C) is a highly conserved gene which encodes the L-type calcium channel subunit in both human and zebrafish. Genetic defects of CACNA1C cause various ECG abnormalities, including long QT, short QT, Brugada, and early repolarization syndromes. Interestingly, a recent study has also revealed CACNA1C mutation is involved in cardiac hypertrophy and fibrosis. Therefore, we hypothesized that L-type calcium channel might be a key factor to attenuate the ECG abnormalities (i.e. arrhythmia, conduction disruption, etc.) following ventricular injury during zebrafish heart regeneration. In this study, we first conducted a time-lapsed gene expression analysis during zebrafish heart regeneration. We observed cacna1c expression significantly decreased by 7 dpi (days post-injury), and then partially recovered by 21 dpi. Next, calcium channel antagonist and agonist drugs were used to treat the zebrafish to reveal how altered activities of the calcium channel will affect the dynamics of cardiac electrical activity during zebrafish heart regeneration. The electrocardiography analysis identified several ECG signatures: QTc interval, PR interval, QRS duration, pathological Q wave and ST-elevation, may serve as biomarkers of zebrafish cardiac electrical activity during regeneration. The findings reveal the association between L-type calcium channel function and electrical remodeling during zebrafish heart regeneration, which highlight calcium signaling pathway and calcium homeostasis may play important roles in regulating cardiac repair during zebrafish heart regeneration.
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