自噬作用為維持心臟機能不可或缺的因子。自噬作用對於外在環境的變化非常敏感，例如高-或低-血糖以及高血壓，在這些生理條件之下，自噬作用的活性會隨之改變，進而達到保護心肌健康的功用。我們發現由Streptozotocin (STZ) 誘導之高血糖動物的心臟組織中，其自噬活性變得非常低並且伴隨細胞凋亡的現象。目前，幹細胞對於心肌細胞自噬作用的影響尚未被廣泛討論，因此在我的實驗裡，將以脂肪間質幹細胞救援受到高血糖傷害的心肌細胞，進而觀察其凋亡存活以及自噬作用的變化。
我們在長期 (24週) 誘導高血糖的動物實驗中，以STZ誘導高血糖（STZ-HG）老鼠，在誘導後的第16週進行間質幹細胞移植，並在誘導後第24週 （6個月）進行犧牲，並觀察自噬作用在心肌中與存活凋亡的關係。我們發現，自噬作用的活性在此類高血糖動物中非常的低，並且也同時觀察到凋亡存活蛋白相對應的上升與下降。 在幹細胞移植治療之後，不只改善了心臟機能，並且抑制了心肌的凋亡，最為驚人的發現為，幹細胞移植除了提升了心肌細胞的存活蛋白表現還同時提升了自噬作用的活性，進而達到保護心肌抵抗高血糖的傷害。
動物體外實驗，我們取用剛出生兩天的新生鼠心臟進行初代培養，之後使用高糖刺激作為實驗組（22 mM, 33 mM）進行培養與控制組 (5 mM) 做比較，觀察凋亡存活自噬相關蛋白質表現。我們在短期（24小時）的高糖刺激實驗中發現，自噬作用相關蛋白大量表現之下，並無任何無任何凋亡蛋白出現。相反的，在長期（72小時）的高糖刺激之下，心肌細胞大量表現凋亡蛋白，自噬作用相關蛋白相較於控制組而言卻接近無表現。在此我們確信，自噬作用唯一種心肌自我保護的機制，在自噬消失時，心肌失去保護，開始走向死亡路徑。
期望在未來，能在心臟疾病臨床治療上，除了投與幹細胞轉譯治療，也可以發展一系列調控自噬作用之藥劑或者療法，例如：轉錄後小分子療法（miRNA），藉由調控自噬作用達到保護心臟功能的效果。
More than half diabetic mellitus patients died due to cardiovascular complications including cardiomyopathy and heart failure that were directly related to hyperglycemia. Autophagy was a cellular process that played an essential role in cytoplasmic homeostasis through degradation and recycling of cellular components. In cardiomyodium, the autophagic activity directly response to stresses such as hyper- or hypoglycemia and hypertension. Up to date, regulation of autophagy in hyperglycemic cardiac muscle remained unclear. Mesenchymal stem cells (MSCs) were known to regulate activity of autophagy in several tissue types such as kidney, liver and lung.In my study, high glucose (HG: 22mM, 33mM) induced neonatal cardiomyocytes (HG-NCM) and STZ-induced hyperglycemia animal. Cardiac tissues and primary cardiomyocytes were utilized to investigate the activity of apoptosis, survival and autophagy pathway. My preliminary results indicated that HG up-regulated components of mitochondrial dependent apoptosis pathway and the formation of autophagosome and autolysophagosome were inhibited in HG heart coupling with apoptosis proteins expression. In this point, we hypothesis that autophagy plays a protector role in long-term HG induction. When MSC therapy was applied to HG-NCM in early stage, survival pathway was promoted via IGF1 signaling pathway. In contrast, autophagic activity were slightly decreased after MSC therapy in early stage. We suggested that the role of protector autophagy was promoted by MSC in early stage HG damage. In long term HG induction, the components of autophagy pathway and the survival pathway were all up-regulated among MSC therapy in vivo and in vitro. These findings demonstrated that autophagy protect cardiac cells from death in hyperglycemia stress in early stage. MSC therapy via IGF1 up-regulated survival potential and may via microRNA ( miRNA ) that remained unknown restored activity of autophagy in HG hearts. We will report the key mediator of miRNA which regulated autophagy, survival and apoptosis signaling pathway in high glucose induction cardiac cells in the next stage.
