Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy
Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy
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DOI：
10.1016/j.biopha.2018.07.126
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发表时间：
2018-11-01
影响因子：
7.5
通讯作者：
Atteya, Muhammad
中科院分区：
文献类型：
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作者：
Al-Damry, Nouf T.;Attia, Hala A.;Atteya, Muhammad
本研究旨在探讨西格列汀（一种二肽基肽酶 4 抑制剂）对糖尿病心肌病 (DCM) 相关细胞凋亡的保护作用，以及这种作用是否是通过调节存活激酶的活性来介导的； AMP 激活蛋白激酶 (AMPK) 和 Akt 及凋亡激酶；糖原合成酶激酶 3 beta (GSK-3 beta) 和 p38 丝裂原激活蛋白激酶 (p38MAPK)。通过单次腹腔注射链脲佐菌素（55 mg/kg）诱发糖尿病。糖尿病大鼠接受西格列汀（10 mg/kg/天，口服）和二甲双胍（200 mg/kg/天，口服作为阳性对照）治疗六周。慢性高血糖导致反映心脏损伤的血清心脏生物标志物升高，这一点得到了 H&E 染色的支持。 I 型和 III 型胶原蛋白的 mRNA 水平升高，反映了心脏纤维化和肥大，这得到了 Masson 毛状体染色和 p38MAPK 磷酸化增强的支持。裂解的 casapse-3、BAX 的心脏蛋白水平升高，而 Bcl-2 和 p-BAD 的水平降低，表明心脏细胞凋亡，这可能归因于糖尿病诱导的 Akt 和 AMPK 磷酸化减少，同时 GSK-3 β 和 p38MAPK 激活增强。 AMPK 上游激酶肝激酶 B-1 的蛋白水平也受到抑制。西格列汀给药减轻了 AMPK 和 Akt 磷酸化的降低，使 GSK-3 β 和 p38 AMPK 失活，因此减轻了糖尿病心脏中高血糖诱导的细胞凋亡和肥大。总之，西他列汀通过减少细胞凋亡在 DCM 治疗中展现出宝贵的治疗潜力。其潜在机制可能涉及 AMPK、Akt、GSK-3 beta 和 p38MAPK 的调节活性。
The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 beta (GSK-3 beta) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3 beta and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3 beta and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3 beta and p38MAPK.