内质网应激在糖尿病心肌病中的研究进展及药物干预

糖尿病心肌病是指发生在糖尿病患者中，在除外高血压性心脏病、冠状动脉粥样硬化性心脏病以及其他心脏结构疾病的情况下，存在左心室功能不全的心肌疾病，主要表现为心脏结构、形态学、功能以及代谢方面的异常。内质网作为一个细胞器，其功能与脂质的合成、钙离子稳态、蛋白质折叠和成熟相关。内质网相关功能的紊乱导致了细胞内的应激反应，称为内质网应激。内质网应激在起始阶段通过未折叠蛋白反应来代偿受损的内质网功能，这个过程主要是通过IRE-1、ATF6、PERK这3种内质网表面跨膜蛋白及其下游促进生存的信号分子来调控的；然而当内质网应激反应过度或者持续时间较长时，未折叠蛋白反应就会启动其下游由CHOP、Caspase-12、JNK介导的凋亡信号通路，最终将会引起细胞凋亡。糖尿病心肌病的发病机制非常复杂，目前研究认为内质网应激与糖尿病心肌病的发生发展相关。高血糖、游离脂肪酸的积累及炎症反应可能是诱发内质网应激的触发因素。为了寻求特异性的治疗方法，近年来国内外学者研究发现许多药物可以通过抑制内质网应激来减少心肌细胞凋亡，改善心脏功能，延缓糖尿病心肌病的发生发展。本文主要针对糖尿病心肌病发展过程中内质网应激作用机制以及不同的药物通过不同的方式来改善内质网应激反应进行综述。 

Review of research progress and drug intervention of endoplasmic reticulum stress in diabetic cardiomyopathy

Diabetic cardiomyopathy(DCM)is defined as the presence of left ventricular dysfunction beyond that which can be accounted for by arterial hypertension,coronary artery disease or evidence of any other structural cardiac disease in individuals with diabetes.DCM is a common consequence of longstanding type 2 diabetes mellitus and encompasses structural,morphological,functional and metabolic abnormalities in the heart.Endoplasmic reticulum(ER) is an organelle entrusted with lipid synthesis,calcium homeostasis,protein folding,and maturation.Perturbation of ER-associated functions results in an evolutionarily conserved cell stress responses,which is called ER stress.ER stress is aimed initially at compensating for damage through three transmembrane proteins including IRE-1,ATF6,PERK and their downstream pro-survival signals,but can eventually trigger cell death if ER stress is excessive or prolonged via apoptotic pathways mediated by CHOP,Caspase-12 and JNK.The mechanisms of the development of diabetic cardiomyopathy are still highly elusive.Now it is known that apoptosis induced by ER stress has been considered to play a role in DCM.Moreover,hyperglycemia,FFAs and inflammation may be the triggers of ER stress.In order to explore the specific therapies for DCM,in recent years scientists from different countries have found that many drugs could alleviate cardiomyocyte apoptosis and improve the function of heart by inhibiting ER stress.Therefore,this paper will summarize the information focused on mechanisms of ER stress in the development of diabetic cardiomyopathy and several drug interventions which can reduce the ER stress by different ways.