GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress
GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress
复制标题
GCN2 缺乏可通过降低脂毒性和氧化应激来改善糖尿病小鼠的心脏功能障碍。
DOI：
10.1016/j.freeradbiomed.2018.10.445
复制
发表时间：
2019-01-01
影响因子：
7.4
通讯作者：
Lu, Zhongbing
中科院分区：
文献类型：
--
作者：
Feng, Wei;Lei, Tong;Lu, Zhongbing
心肌脂质过度积聚是糖尿病性心肌病（DCM）的主要特征。虽然一般控制非去阻遏蛋白2（GCN 2）已被确定为氨基酸利用率的传感器，它也作为一个重要的调节肝脏脂质代谢。我们以前的研究报道，GCN 2通过增加心肌细胞凋亡和心肌氧化应激促进压力超负荷或阿霉素诱导的心功能不全。然而，GCN 2对DCM发展的影响仍不清楚。在这项研究中，我们研究了GCN 2对1型和2型糖尿病动物模型中DCM的影响。经链脲佐菌素（STZ）或高脂饮食（HFD）加低剂量STZ治疗后，GCN 2（-/-）小鼠与野生型（WT）小鼠相比，心功能不全、高脂血症、心肌肥大、纤维化、脂质蓄积、氧化应激、炎症和细胞凋亡发生率降低。在糖尿病心脏中，GCN 2缺乏减弱了过氧化物酶体增殖物激活受体α（PPAR α）和γ（PPAR γ）的上调，eIF2 α的磷酸化和激活转录因子4（ATF 4）和C/EBP同源蛋白（CHOP）的诱导，以及Bcl-2的减少。此外，我们发现，敲低GCN 2减弱，而过度表达GCN 2加剧，高糖或棕榈酸诱导的细胞死亡，氧化和内质网应激和脂质积累在H9C2细胞。总的来说，我们的数据提供了证据表明，GCN 2缺乏通过减少脂质积累，氧化应激和细胞死亡来保护心脏功能。我们的研究结果表明，抑制心脏GCN 2活性的策略可能是DCM治疗的新方法。
Excessive myocardial lipid accumulation is a major feature of diabetic cardiomyopathy (DCM). Although general control nonderepressible 2 (GCN2) has been identified as a sensor of amino acid availability, it also functions as an important regulator of hepatic lipid metabolism. Our previous studies have reported that GCN2 promotes pressure overload or doxorubicin-induced cardiac dysfunction by increasing cardiomyocyte apoptosis and myocardial oxidative stress. However, the impact of GCN2 on the development of DCM remains unclear. In this study, we investigated the effect of GCN2 on DCM in type 1 and type 2 diabetes animal models. After streptozotocin (STZ) or high-fat diet (HFD) plus low-dose STZ treatments, GCN2(-/-) mice developed less cardiac dysfunction, hyperlipidemia, myocardial hypertrophy, fibrosis, lipid accumulation, oxidative stress, inflammation and apoptosis compared with wild-type (WT) mice. In diabetic hearts, GCN2 deficiency attenuated the upregulation of peroxisome proliferator-activated receptor alpha (PPAR alpha) and gamma (PPAR gamma), the phosphorylation of eIF2 alpha and the induction of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), as well as the reduction of Bcl-2. Furthermore, we found that knockdown of GCN2 attenuated, whereas overexpression of GCN2 exacerbated, high glucose or palmitic acid-induced cell death, oxidative and endoplasmic reticulum stress and lipid accumulation in H9C2 cells. Collectively, our data provide evidence that GCN2 deficiency protects cardiac function by reducing lipid accumulation, oxidative stress and cell death. Our findings suggest that strategies to inhibit GCN2 activity in the heart may be novel approaches for DCM therapy.