从心肌细胞自身稳态调控角度寻找对抗心肌缺血再灌注损伤(myocardial ischemia-reperfusion injury，MIRI)的调控分子，是目前MIRI防治研究的一个热点。溶酶体是细胞自噬的效应器，它能迅速清除细胞内受损组份、对细胞能量和代谢物质进行再分配，在对抗心肌细胞应激损伤中发挥重要作用。CREG蛋白是成熟心肌细胞中高表达的溶酶体相关蛋白，其在溶酶体中的调控作用和机制尚不明确。本室和其他研究都证实，过表达CREG对高血压心肌肥大和心肌纤维化中具有保护作用。并且，本室前期预实验研究发现，CREG对MIRI造成的心功能损伤具有明确的保护作用。因此，本研究尝试从心肌细胞的自噬-溶酶体的调控角度入手，通过在体小鼠MIRI模型、离体心和原代心肌细胞研究,分别阐明CREG对抗MIRI后心肌损伤的作用机制和分子调控网络，以期为MIRI损伤的防治研究提供新的研究思路和干预因子。

Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. Reperfusion of the ischemic myocardium by primary percutaneous coronary intervention is essential to minimize myocardial damage; however, restoration of blood flow may paradoxically result in myocardial ischemia/reperfusion injury (MIRI). MIRI is characterized by metabolic disorder, local inflammatory response, cell death and subsequent cardiac remodeling and dysfunction that contributes to adverse cardiac events after myocardial ischemia, cardiac surgery, or cardiogenic shock. In recent years, targeting individual mediators of lethal reperfusion injury has produced discrepant findings in animal studies, and clinical studies that use this strategy have been unsuccessful. Therefore, a better understanding of these processes and mechanisms that promote MIRI is critical to finding effective treatment in patients with IHD. Autophagy is a well-conserved intracellular lysosomal degradation process essential for cellular homeostasis, cell defense and cell adaptation to an adverse environment. Autophagy allows the cells not only to recycle amino acids but also to remove damaged organelles, thereby eliminating oxidative stress and allowing cellular remodeling for survival. In recent years, emerging research has shown that autophagy is rapidly induced in the myocardium in response to stress conditions such as fasting, pressure overload and MIRI. Therefore, exploring the mechanisms of cardiomyocyte autophagy might shed new light on treatment of MIRI. Human cellular repressor of E1A-stimulated genes (CREG) is a secreted glycoprotein that regulates tissue and cell homeostasis and has been shown to antagonize heart fibrosis, which indicates a potential protective effect of CREG against cardiomyocyte chronic damage. However, little is known about the role of CREG in myocardial tissue acute injury, in this study, we aimed to investigate the role of CREG in MIRI and clarify the mechanism of action. Wild-type Creg, myocardiac conditional knock-out CREG (Creg-CKO) mice and CREG transgenic mice (Tg-CREG) were subjected to 30 min of left ascending coronary ischemia and 24 h of reperfusion. Evan's Blue-triphenyl- tetrazolium chloride (TTC) solution and echocardiography analysis were used to evaluate the effects of CREG on MIRI mice. Furthermore, chloroquine and 3-MA, as the autophagy blocker, were used to demonstrate Tg-CREG protected cardiomyocytes mediated by activating autophagy-lysosome pathway in vivo. The underlying mechanisms were further determined by langendorff instrument and cultured myocardial cells ex vivo and in vitro. These studies try to demonstrate that overexpression of CREG could protect heart against MIRI by activating autophagy-lysosome pathway, which might be a novel therapeutic target for patients suffering from MIRI.