“钠尿肽-内质网稳态”失衡在糖尿病心肌缺血损伤中的作用及其机制的研究

Diabetes mellitus is easy to be complicated by myocardial ischemia. Endoplasmic reticulum stress (ERS) is the key link of diabetic ischemic myocardial injuries. We found that natriuretic peptides (NPs) protected diabetic ischemic myocardium by suppressing ERS via NPR-cGMP-PKG signaling pathway. Also, our preliminary experiments showed impaired NPs signal in ERS rats induced by tunicamycin, and ERS inhibitors TUDCA could partially restore the decreased activity of NPs signal. It suggests that there is cross regulation between endoplasmic reticulum and NPs signals, and “NPs-endoplasmic reticulum homeostasis” maintains the normal structure and function of the heart. The disbalance of “NPs-endoplasmic reticulum homeostasis” might be an important cause of injuries in the diabetic ischemic myocardium. However, the underlying mechanism is not clear. The current study is to investigate the cardiac ERS, as well as its relationship with NPs signal, in the type 2 diabetic rats with myocardial ischemia, or in the mice with conditionally knocked-out NPRA in the myocardium, respectively. Moreover, with the regulation of “NPs-endoplasmic reticulum homeostasis” as a breakthrough point, the diabetic rats with myocardial ischemia were given aerobic exercise intervention, in order to confirm the scientific hypothesis of disbalance of “NPs-endoplasmic reticulum homeostasis” in diabetic ischemic myocardium. The present study is supposed to reveal a novel mechanism of myocardial injuries in the diabetic ischemic myocardium, providing new strategies for the prevention and treatment of diabetic ischemic heart disease.

糖尿病易并发心肌缺血，内质网应激（ERS）是糖尿病心肌缺血损伤的重要环节。我们发现钠尿肽经NPR-cGMP-PKG通路抑制ERS，保护糖尿病缺血心肌。预实验还显示，在衣霉素诱导的ERS大鼠，心肌钠尿肽信号受损，而ERS抑制剂可部分恢复钠尿肽信号的活性。提示，内质网与钠尿肽信号交互调节，“钠尿肽-内质网稳态”维持心脏的正常结构与功能。而“钠尿肽-内质网稳态”失衡可能是糖尿病心肌缺血损伤的重要原因，但其机制不明。本课题拟分别采用2型糖尿病心肌缺血大鼠、ERS大鼠和心肌条件性敲除钠尿肽NPRA受体的小鼠，观察心肌ERS的情况，及其与钠尿肽信号之间的关系。进而，以“钠尿肽-内质网”稳态调节为切入点，给予糖尿病心肌缺血大鼠有氧运动的干预，进一步证实糖尿病缺血心肌“钠尿肽-内质网稳态”失衡的科学假说。这将揭示糖尿病心肌缺血损伤的新机制，并为防治糖尿病缺血性心脏病提供新的策略。

糖尿病易并发心肌缺血，内质网应激（ERS）是糖尿病心肌缺血性损伤的重要环节。我们前期发现钠尿肽经NPR-cGMP-PKG通路抑制ERS，保护糖尿病缺血心肌。在衣霉素诱导的ERS大鼠，心肌钠尿肽信号受损，而ERS抑制剂可部分恢复钠尿肽信号的活性。提示，内质网与钠尿肽信号交互调节“钠尿肽-内质网稳态”，维持心脏的正常结构与功能。而“钠尿肽-内质网稳态”失衡是糖尿病心肌缺血损伤的重要原因。本课题分别采用2型糖尿病心肌缺血大鼠、ERS大鼠和心肌条件性敲除钠尿肽NPRA受体的小鼠，观察了心肌ERS的情况，及其与钠尿肽信号之间的关系。进而，以“钠尿肽-内质网”稳态调节为切入点，给予糖尿病心肌缺血大鼠有氧运动的干预。研究发现，（1）钠尿肽可以减弱糖尿病缺血/再灌注（ischemia/reperfusion，I/R）大鼠心肌的ERS，保护心肌。该效应被8-Br-cGMP（一种膜通透性的cGMP类似物）所模拟，被PKG的拮抗剂KT-5823所抑制。（2）衣霉素诱导的ERS大鼠心肌，BNP上调的同时，cGMP/BNP的比值却显著降低。（3）NPRA敲除小鼠心肌的ERS标志性蛋白GRP78、CHOP表达上调，并伴有心肌凋亡加重，ROS水平升高，以及代谢异常。（4）有氧运动可改善糖尿病小鼠心肌损伤，其机制与抑制氧化应激、降低内质网应激和激活cGMP-PKG信号通路有关。上述结果证实了糖尿病缺血心肌“钠尿肽-内质网稳态”失衡的科学假说，揭示了糖尿病心肌缺血损伤的新机制，并为防治糖尿病缺血性心脏病提供了新的策略。