Survivin在心肌再生中扮演的角色

Abstract

心肌梗塞（心臟病發作）為心血管疾病中最致命的死因之一，而心血管疾病在台灣十大死因中長居第二排名。雖然目前在臨床上已經有血管再灌注手術以及藥物的治療，但是由於成人心臟所具有的復原能力非常微弱，病人在接受治療之後仍然有很高的機率會面臨到慢性心臟衰竭的危害。因此除了傳統的治療方式之外，搭配基因治療具有能夠更有效的解決心肌梗塞病人所可能遭遇到的長期問題之潛力。 Survivin是抑制細胞凋亡家族（inhibitor of apoptosis family）中最小的成員。Survivin除了具有在細胞凋亡過程中能夠抑制凋零蛋白酶-9（caspase-9）活化的能力，也具備在細胞分裂中調控染色體分離的功能。之前的研究發現在心肌細胞專一survivin基因剔除鼠中，缺少survivin會造成心肌細胞不完整的細胞分裂進而影響到心臟的發育。然而，survivin在心肌梗塞之後心肌細胞中的功能仍然不清楚。 在研究中，我們建立了誘發性心肌細胞專一survivin基因剔除鼠。在此基因剔除鼠中我們發現缺血心肌組織周圍有30.8%的心肌細胞進行細胞凋亡，明顯高於在對照組老鼠中只有22.2%的比例。術後21天對照組老鼠具有38.0%的心室輸出容積比例（ejection fraction），而基因剔除鼠卻降至29.0%。當我們在老鼠的心肌細胞細胞質中大量表現survivin，老鼠在心肌梗塞後相較於對照組，會有較高的心室輸出容積比例、較少的心肌細胞凋亡、以及較低比例的凋零蛋白酶-3活化。然而，心肌細胞細胞核內有大量的survivin表現，可以在術後的老鼠發現更多的心肌細胞增殖，而這樣的結果是survivin經由與Aurora B的交互作用造成。 在我們的研究中，我們展示了survivin在心肌細胞中不同的位置會具有不同的功能，而survivin在心肌細胞中所扮演的角色也與心肌梗塞後的回復有著相當重要的關聯。在未來，配合著心肌細胞專一以及較少免疫反應的給予方式，survivin非常具有潛力應用在心肌梗塞的臨床治療。

Myocardial infarction, commonly known as heart attack, is a possibly fatal result of cardiovascular disease, which is the second leading cause of death in Taiwan. Even though catheter-based and surgical revascularization plus pharmacological therapies are available for patients with acute myocardial infarction, a substantial portion of patients develop heart failure, with poor cardiac regeneration. Therefore, for such patients, novel and advanced therapies are needed; among the foreseeable possibilities, gene therapy is a good candidate. Survivin is the smallest member of the inhibitor of apoptosis family. It has two important functions; inhibition of caspase-9 activation during apoptosis, and regulation of chromosome segregation during cell division. Genetic depletion of cardiac survivin leads to incomplete cardiomyocyte division and abnormal heart development. However, the function of survivin in adult hearts after myocardial infarction remains unclear. We found that 30.8% of cardiomyocytes in the peri-infarct region of inducible cardiomyocyte-specific survivin knockout mice were apoptotic, a significantly higher percentage than 22.2% in control mice. Ejection fraction was 29.0% in knockout mice compared to 38.0% in control mice 21 days after MI. However, mice overexpressing cytosolic survivin maintained a 8.7% higher ejection fraction, had 4.7% fewer apoptotic cardiomyocytes, and showed reduced activation of caspase-3 compared to control mice. Moreover, mice overexpressing survivin contained a nuclear localization sequence and exhibited enhanced cardiomyocyte proliferation through interaction with Aurora B. Here, we demonstrate the importance of survivin subcellular localization in regulating post-MI cardiac repair and regeneration, and show the translational potential of targeted delivery of survivin. Its cardiac-specific regulation of expression coupled with less immune responsive gene delivery, suggests that survivin is a potential future clinical therapeutic candidate in the treatment of myocardial infarction.