| Summary: | 博士 === 國立交通大學 === 生物科技系所 === 96 === Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. AF appears to be a progressive disease and to be self-sustaining through alterations in atrial tissue properties. The processes leading to the worsening of AF over time were characterized by electrical, contractile and structural changes, referred to as atrial remodeling. However, the underlying mechanisms involved in the remodeling of atria with AF are incompletely defined. Additionally, the knowledge of molecular mechanisms responsible for the atrial remodeling of AF inevitably require further investigation to improve the clinical management of AF and the efficacy of therapy. In this study, a rapid atrial pacing (RAP)-induced AF model was employed to investigate the alteration of the gene expression profile and the expression and activity of matrix metalloproteinases or tissue inhibitors of metalloproteinases in the atria with AF for addressing the remodeling processes at molecular level.
This thesis is comprised of two parts. The first one investigates gene expression responses obtained from a low-density cDNA array in the porcine atria with fibrillation. We identified 31 genes involved in transcriptional regulation, signal transduction or structural components, which were either significantly upregulated or downregulated in the atria with AF. The genes for four and a half LIM domains protein-1 (FHL1), transforming growth factor-β (TGF-β)-stimulated clone 22 (TSC-22), and cardiac ankyrin repeat protein (CARP) were significantly upregulated, and chromosome 5 open reading frame gene 13 (P311) was downregulated in the fibrillating atria. FHL1 and CARP play important regulatory roles in cardiac remodeling by transcriptional regulation and myofilament assembly. Induced mRNA expression of both FHL1 and CARP was also observed when cardiac H9c2 cells were treated with an adrenergic agonist. Increasing TSC-22 and marked P311 deficiency could enhance the activity of TGF-β signaling and the upregulated TGF-β1 and -β2 expressions were identified in the fibrillating atria. The results presented in the first part suggest that observed alterations of underlying molecular events were involved in the rapid-pacing induced AF, possibly via activation of the β-adrenergic and TGF-β signaling.
The second part focuses on the mechanisms responsible for the atrial extracellular matrix (ECM) remodeling in atrial fibrillation. The major findings presented in this part indicated the localization and alteration in profile of matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) expression in the atrial myocardium with AF. The striking increase in gelatinase activity was found in the AF, which might be associated with the activation of TGF-��1 and contribute to ECM remodeling and fibrosis in the atrium. In addition, the increase in TIMP inhibitory activity in the fibrillating atria may provide regulation of proMMP-9 activation and inhibition of the activated MMPs through their inhibitory ability or complexes with proMMP-9. Another important finding was that TIMP-1 mostly colocalized with gelatinase activity over the AF tissues, showing the coexistence of gelatinase activity and TIMP-1; however, TIMP-3 appeared only partial colocalization and to discontinue the gelatinase activity surrounding the cardiomyocytes, revealing that TIMP-1 and TIMP -3 may play a differential role in inhibiting the gelatinase in vivo. The identification of changes in certain species of MMP and TIMP as well as their in vivo interplay in the RAP-induced AF model may improve understanding of the pathophysiology of atrial remodeling and fibrillation.
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