Exendin-4 and Liraglutide Attenuate Glucose Toxicity-Induced Cardiac Injury through mTOR/ULK1-Dependent Autophagy.

Mitochondrial injury and defective autophagy are common in diabetic cardiomyopathy. Recent evidence supports benefits of glucagon-like peptide-1 (GLP-1) agonists exendin-4 (Exe) and liraglutide (LIRA) against diabetic cardiomyopathy. This study was designed to examine the effect of Exe and LIRA on glucose-induced cardiomyocyte and mitochondrial injury, oxidative stress, apoptosis, and autophagy change. Cardiomyocytes isolated from adult mice and H9c2 myoblast cells were exposed to high glucose (HG, 33 mM) with or without Exe or LIRA. Cardiac contractile properties were assessed including peak shortening, maximal velocity of shortening/relengthening (±dL/dt), time to PS, and time-to-90% relengthening (TR90). Superoxide levels, apoptotic proteins such as cleaved caspase-3, Bax, and Bcl-2, and autophagy proteins including Atg5, p62, Beclin-1, LC3B, and mTOR/ULK1 were evaluated using Western blot. Mitochondrial membrane potential (MMP) changes were assessed using JC-1, and autophagosomes were determined using GFP-LC3. Cardiomyocyte exposure to HG exhibited prolonged TR90 associated with significantly decreased PS and ±dL/dt, the effects of which were partly restored by GLP-1 agonists, the effects of which were negated by the mTOR activator 3BDO. H9c2 cell exposure to HG showed increased intracellular ROS, apoptosis, MMP loss, dampened autophagy, and elevated p-mTOR and p-ULK1, the effects of which were nullified by the GLP-1 agonists. These results suggested that GLP-1 agonists rescued glucose toxicity likely through induction of mTOR-dependent autophagy.

线粒体损伤和自噬缺陷在糖尿病性心肌病中很常见。近期有证据支持胰高血糖素样肽 - 1（GLP - 1）激动剂艾塞那肽 - 4（Exe）和利拉鲁肽（LIRA）对糖尿病性心肌病有益。本研究旨在检测Exe和LIRA对葡萄糖诱导的心肌细胞和线粒体损伤、氧化应激、细胞凋亡以及自噬变化的影响。从成年小鼠分离的心肌细胞和H9c2成肌细胞在有或无Exe或LIRA的情况下暴露于高葡萄糖（HG，33 mM）环境中。评估心脏收缩特性，包括收缩峰值、收缩/舒张最大速率（±dL/dt）、达到收缩峰值的时间以及达到90%舒张的时间（TR90）。使用蛋白质印迹法评估超氧化物水平、凋亡蛋白（如裂解的半胱天冬酶 - 3、Bax和Bcl - 2）以及自噬蛋白（包括Atg5、p62、Beclin - 1、LC3B和mTOR/ULK1）。使用JC - 1评估线粒体膜电位（MMP）变化，使用GFP - LC3测定自噬体。心肌细胞暴露于HG时，TR90延长，同时收缩峰值和±dL/dt显著降低，GLP - 1激动剂可部分恢复这些影响，而mTOR激活剂3BDO可抵消这些影响。H9c2细胞暴露于HG时，细胞内活性氧增加、细胞凋亡、MMP丧失、自噬减弱，p - mTOR和p - ULK1升高，GLP - 1激动剂可消除这些影响。这些结果表明，GLP - 1激动剂可能通过诱导mTOR依赖性自噬来挽救葡萄糖毒性。