| Abstract: | 心臟缺血(Ischemia)、缺氧(Hypoxia)會造成許多心臟疾病，如心肌梗塞、充血性心臟衰竭(congestive heart failure)、動脈硬化(atherosclerosis)、冠狀阻塞(coronary occlusion)等。心臟缺血會導致心肌細胞減少氧氣的供給進而造成心房顫動 (atrial fibrillation, AF)，使心肌細胞損傷，進而促使心臟重組 (cardiac remodeling)、纖維化(fibrogenesis)，最終導致心衰竭(heart failure)。而有許多文獻指出，心房顫動會增加缺氧(hypoxia)的相關指標及血管新生指標因子的表現，進而促使缺氧誘導因子(hypoxia-inducible factor, HIF)的大量表現。而心房顫動的另一個特徵，則是具有心臟纖維化(cardiac fibrosis)及細胞外基質(exteracelluar matrix, ECM)改變以及心肌細胞肥大(hypertrophy)的特徵。此特徵會促使纖維化的部位會有大量的細胞外基質的沉積。而目前也有研究指出當心肌處與缺氧壓力下，會刺激心臟細胞活化低氧誘導因子來調控相關基因表現，以保護心肌細胞。微型核醣核酸(miRNA, microRNA)為一種有效調控基因表現的單鏈小RNA分子，參與在疾病生理調控機制上，目前在心臟疾病上已經被廣泛地探討，但是以目前的研究，在心肌缺氧壓力下所導致的心房顫動進而促使心臟重構及纖維化的因果關係中，其作用的相關機轉仍不清楚。 目前本實驗室發現留鹽激素 留鹽激素 留鹽激素 留鹽激素 (Aldosterone)可以透過已知醛固酮受體(mineralocorticoid receptor, MR)，進而調控下游的MAPK pathway，促使 TGF-β1, collagen type IA, collagen type IIIA及-SMA等纖維化因子的大量表現，此研究已發表在International Journal of Cardiology。而且，本實驗室也發現在缺氧壓力下，會促使心肌細胞纖維化因子的表現。然而，其心肌細胞纖維化的詳細調控機制仍不清楚，本實驗室已利用microRNA microarray初步篩選缺氧心肌細胞內與調控纖維化因子表現相關的miRNA，如miR-29b等。因此，本計畫目的是探討miRNA在心肌細胞於缺氧壓力下，其不同miRNA的調控，並觀察其表現程度以分辨、診斷疾病，更可以進一步發展出以miRNA為治療標的之藥物。
Ischemia (reduced blood flow) and hypoxia (reduced oxygen) are mainly subject in cardiology, occur in myocardial infarction, congestive heart failure, atherosclerosis, coronary occlusion or surgery. The deficient oxygen supply may result in myocardial dysfunction, promote cardiac remodeling and fibrogenesis and leading to development of heart failure on the ventricular level and dysrhythmias like atrial fibrillation, which is raised by selective atrial ischemia. In atrial fibrillation, the increased expression of hypoxic and angiogenic markers are found, and also proven the up-regulation of the hypoxia-inducible factor (HIF) pathway and paralleled by fibrogenesis in atrial myocardium. The cardiac remodeling, characterized by cardiac fibrosis, exteracelluar matrix (ECM) deposition and hypertrophy is the important pathological feature of the failing heart. Abundant deposition of ECM is found in the maturation of fibrosis, and the ratio of collagen type I increases in fibrosis. Moreover, in respond to hypoxia, several HIF-1α-regulated cardioprotective genes have been reported. There is a need for a better understanding of the causes and consequences of hypoxia, and for the development of atrial fibrillation and cardiac remodeling (i.e., fibrosis). However, recent studies indicate microRNA, short RNA sequences of 18-25 nucleotides, play an importance role in myocardial disease. In the past few years, several miRNA were found to regulate heart diseases such as cardiac hypertrophy, heart failure, remodeling, growth and fibrosis. The role of miRNA in cardiac fibrosis induced by hypoxia and atrial fibrillation has only just to unravel. Our lab has reported that aldosterone could modulate TGF-β1, collagen type IA, collagen type IIIA and -SMA protein expression through MAPK pathway. Moreover, we discover the fibrosis factors are modulated by hypoxia stress. Next, we found some miRNA such as miR-29b test by miRNA microarray of hypoxia cardiac cell is associated with fibrosis marker. Herein, the aim of this study hypothesize that miRNA may regulate cardiac fibrosis induced by atrial fibrillation in hypoxia stress, and evaluate the molecular alteration regulated by miRNA. Finally, perspectives on future direction of research and therapeutic method on hpoxia in atrial fibrillation are provided. |
