Carvacrol Attenuates Diabetic Cardiomyopathy by Modulating the PI3K/AKT/GLUT4 Pathway in Diabetic Mice
Carvacrol Attenuates Diabetic Cardiomyopathy by Modulating the PI3K/AKT/GLUT4 Pathway in Diabetic Mice
复制标题
香芹酚通过调节糖尿病小鼠的 PI3K/AKT/GLUT4 通路减轻糖尿病心肌病
DOI：
10.3389/fphar.2019.00998
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发表时间：
2019-09-12
影响因子：
5.6
通讯作者：
Luo, Jian-dong
中科院分区：
文献类型：
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作者：
Hou, Ning;Mai, Yunpei;Luo, Jian-dong
背景：糖尿病心肌病(DCM)是糖尿病的常见并发症，最终导致心力衰竭。香芹酚是一种具有多种生物活性的食品添加剂。本研究旨在探讨香芹酚对扩张型心肌的保护作用及其机制。方法：采用链脲佐菌素诱导的1型糖尿病(T1 DM)和2型糖尿病(T2 DM)db/db小鼠模型。两个研究组每天都接受6周的香芹酚腹腔注射。通过组织学分析评价心脏重塑。用实时定量聚合酶链式反应检测心脏重塑标志物NPPA和Myh7的基因表达，超声心动图检测心功能。Western blotting检测PI3K/AKT信号的变化。用Western blotting和免疫荧光染色检测GLUT4易位。结果：与对照组相比，T1 DM和T2 DM小鼠均出现心脏重构和左心功能不全。香芹酚显著降低T1 DM和T2 DM小鼠的血糖水平并抑制心脏重塑。在治疗结束时，与只服用赋形剂的小鼠相比，T1 DM和T2 DM小鼠的心肌肥厚、NPPA和Myh7 mRNA的表达以及心肌纤维化程度都较轻。此外，香芹酚显著恢复了T1 DM和T2 DM小鼠受损的PI3K/AKT信号转导。香芹酚增加T1 DM和T2 DM小鼠PI3K、PDK1、AKT和AS160的磷酸化水平，并抑制PTEN的磷酸化。香芹酚治疗可促进T1 DM和T2 DM小鼠GLUT4膜转位。以二甲双胍作为T2 DM小鼠的阳性药物对照，香芹酚对心肌重塑和信号转导通路的调节作用与二甲双胍相当。结论：香芹酚通过恢复PI3K/AKT信号转位介导的GLUT4膜转位，对T1 DM和T2 DM小鼠DCM具有保护作用，是一种潜在的治疗DCM的方法。
Background: Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus, eventually leads to heart failure. Carvacrol is a food additive with diverse bioactivities. We aimed to study the protective effects and mechanisms of carvacrol in DCM. Methods: We used a streptozotocin-induced and db/db mouse model of types 1 and 2 diabetes mellitus (T1DM and T2DM), respectively. Both study groups received daily intraperitoneal injections of carvacrol for 6 weeks. Cardiac remodeling was evaluated by histological analysis. We determined gene expression of cardiac remodeling markers (Nppa and Myh7) by quantitative real-time PCR and cardiac function by echocardiography. Changes of PI3K/AKT signaling were determined with Western blotting. GLUT4 translocation was evaluated by Western blotting and immunofluorescence staining. Results: Compared with control mice, both T1DM and T2DM mice showed cardiac remodeling and left ventricular dysfunction. Carvacrol significantly reduced blood glucose levels and suppressed cardiac remodeling in mice with T1DM and T2DM. At the end of the treatment period, both T1DM and T2DM mice showed lesser cardiac hypertrophy, Nppa and Myh7 mRNA expressions, and cardiac fibrosis, compared to mice administered only the vehicle. Moreover, carvacrol significantly restored PI3K/AKT signaling, which was impaired in mice with T1DM and T2DM. Carvacrol increased levels of phosphorylated PI3K, PDK1, AKT, and AS160 and inhibited PTEN phosphorylation in mice with T1DM and T2DM. Carvacrol treatment promoted GLUT4 membrane translocation in mice with T1DM and T2DM. Metformin was used as the positive drug control in T2DM mice, and carvacrol showed comparable effects to that of metformin on cardiac remodeling and modulation of signaling pathways. Conclusion: Carvacrol protected against DCM in mice with T1DM and T2DM by restoring PI3K/AKT signaling-mediated GLUT4 membrane translocation and is a potential treatment of DCM.