High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of biological processes. However, its effect on cardiac remodeling (refer to cardiac inflammation, apoptosis and dysfunction) in diabetic cardiomyopathy remains largely indistinct. In this study, we found that HMGA1 was upregulated in diabetic mouse hearts and high-glucose-stimulated cardiomyocytes. Overexpression of HMGA1 accelerated high-glucose-induced cardiomyocyte inflammation and apoptosis, while HMGA1 knockdown relieved inflammation and apoptosis in cardiomyocytes in response to high glucose. Overexpression of HMGA1 in mice heart by adeno-associated virus 9 (AAV9) delivery system deteriorated the inflammatory response, increased apoptosis and accelerated cardiac dysfunction in streptozotocin-induced diabetic mouse model. Knockdown of HMGA1 by AAV9-shHMGA1 in vivo ameliorated cardiac remodeling in diabetic mice. Mechanistically, we found that HMGA1 inhibited the formation rather than the degradation of autophagy by regulating P27/CDK2/mTOR signaling. CDK2 knockdown or P27 overexpression blurred HMGA1 overexpression-induced deteriorating effects in vitro. P27 overexpression in mice heart counteracted HMGA1 overexpression-induced increased cardiac remodeling in diabetic mice. The luciferase reporter experiment confirmed that the regulatory effect of HMGA1 on P27 was mediated by miR-222. In addition, a miR-222 antagomir counteracted HMGA1 overexpression-induced deteriorating effects in vitro. Taken together, our data indicate that HMGA1 aggravates diabetic cardiomyopathy by directly regulating miR-222 promoter activity, which inhibits P27/mTOR-induced autophagy.

中文翻译：

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高机动性组AT-hook 1通过自噬抑制促进糖尿病性心肌病的心脏功能障碍。

高迁移率的AT-hook1组（HMGA1，以前称为HMG-I / Y）是一种建筑转录因子，参与许多生物学过程。然而，它对糖尿病性心肌病中心脏重塑（指心脏炎症，细胞凋亡和功能障碍）的影响仍不清楚。在这项研究中，我们发现HMGA1在糖尿病小鼠心脏和高糖刺激的心肌细胞中上调。HMGA1的过表达加速了高葡萄糖诱导的心肌细胞炎症和细胞凋亡，而HMGA1的敲低缓解了高糖对心肌细胞的炎症和细胞凋亡。腺相关病毒9（AAV9）递送系统在小鼠心脏中过表达HMGA1会恶化链脲佐菌素诱导的糖尿病小鼠模型的炎症反应，细胞凋亡增加和心脏功能障碍。体内通过AAV9-shHMGA1敲除HMGA1可改善糖尿病小鼠的心脏重塑。从机理上讲，我们发现HMGA1通过调节P27 / CDK2 / mTOR信号传导抑制自噬的形成而不是自噬的降解。CDK2敲低或P27过表达模糊了HMGA1过表达诱导的体外恶化作用。小鼠心脏中的P27过表达抵消了HMGA1过表达诱导的糖尿病小鼠心脏重塑增加。荧光素酶报告基因实验证实，HMGA1对P27的调节作用是由miR-222介导的。另外，miR-222 antagomir在体外抵消了HMGA1过表达诱导的恶化作用。综上所述，我们的数据表明HMGA1通过直接调节miR-222启动子活性（加重P27 / mTOR诱导的自噬）来加重糖尿病性心肌病。