顾晨，李俊明



内质网应激致2型糖尿病缺血心肌易损性增强的机制研究

顾晨，李俊明

摘要

Mechanism of Increased Myocardial Ischemic Vulnerability in Mice Type 2 Diabetes Mellitus Induced by Endoplasmic Reticulum Stress

GU Chen, LI Jun-ming.
Three Gorges University People’s Hospital, Yichang (443002), Hubei, China
Corresponding Author: LI Jun-ming, Email: lijunming@medmail.com.cn

Abstract

Objective: To study the relationship between endoplasmic reticulum stress (ERS) and adiponectin; to explore the role of ERS for increasing myocardial ischemic vulnerability in type 2 diabetes mellitus (DM) mice.

Methods: Type 2 DM model was established by high fat diet with streptozotocin (STZ) injection. A total of 35 C57BL/6J male type 2 DM mice were divided into 4 groups: ①Control group, n=5. ②Tauroursodeoxycholic acid (TUDCA) group, ③Thapsigargin (TG) group and ④Normal saline group. The mice in Groups ②, ③, ④ were fed by high fat and high glucose diet by injecting streptozotocin (STZ), in the last 3 weeks and respectively received intraperitoneal injections of TUDCA (250 mg/kg), thapsigargin (TG) (300 μg/kg) and normal saline twice a day, n=10 in each group. Then myocardial infarction (MI) model was established in 5 mice from each group. 72 hours later, the MI ranges were measured, serum levels of adiponectin were detected, mRNA expressions of adiponectin and CHOP in myocardial tissue were examined.

Results: The MI range in TUDCA group (21.47 ± 2.85) % and in Normal saline group (39.92 ± 4.28) % were both lower than TG group (66.56 ± 8.15) %, both P<0.01. Before MI occurrence, serum levels of adiponectin in TUDCA group (79.25 ± 6.40) pg/ml and in Normal saline group (70.23 ± 4.15) pg/ml were both higher than TG group (62.64 ± 5.70) pg/ml,both P<0.01; serum levels of adiponectin in each group were higher than they were 72 h after MI. In each group, the mRNA expression and protein content of adiponectin in myocardial tissue were constant to serum adiponectin; while the mRNA expression and protein content of CHOP was opposite to serum adiponectin.

Conclusion: ESR could increase myocardial vulnerability in type 2 DM mice which might be related to down-regulating adiponectin expression.

Key words Diabetes mellitus, Type 2; Endoplasmic reticulum; stress; Myocarial ischemia

(Chinese Circulation Journal, 2016,31:91.)

高血糖和高脂血症不仅导致血管损伤从而诱发缺血性心脏病，且直接损害心肌细胞，导致在缺血再灌注后更广泛的心肌梗死和更严重的心力衰竭[1-5]。脂联素是一种主要由脂肪组织合成、分泌的脂肪细胞因子，具有调节代谢、抗炎及心血管保护作用，血清脂联素水平降低能导致心肌纤维化的发生、发展[6]。多项研究表明糖尿患者血浆脂联素水平降低可能是导致缺血性心脏病的关键因素[7，8]。脂联素通过多个信号通路发挥其心血管的保护作用[9]。因此，上调脂联素水平能够减轻糖尿病心肌缺血损伤，但对于脂联素的上游调节机制仍不是很清楚。缺氧等多种因素导致未折叠或错误折叠蛋白质在内质网腔蓄积，致使内质网功能发生改变，统称内质网应激（ERS）[10-12]。而牛磺脱氧胆酸（TUDCA）是一种缓解ERS的化学分子伴侣，能减轻ERS状态下的巨噬细胞的脂质蓄积[13]，毒胡萝卜内酯是一种通过抑制内质网Ca2+-ATP酶导致ERS的化学抑制剂。凋亡相关蛋白C/EBP 同源蛋白（CHOP）是ERS的一种特征性标志分子。心肌缺血/再灌注损伤（IRI）时，ERS信号通路被激活，分子伴侣以及促凋亡信号分子表达增加[14-16]。TUDCA能降低CHOP的表达即缓解ERS，明显缓解毒胡萝卜内酯所引起的脂联素水平的下调[17]。

基于上述研究结果，我们提出假设：2 型糖尿病心肌缺血可以引发ERS，ERS加重可下调血浆与心肌脂联素水平，进而导致缺血心肌易损性增加。……