Dipeptidyl peptidase IV inhibition upregulates GLUT4 translocation and expression in heart and skeletal muscle of spontaneously hypertensive rats
Dipeptidyl peptidase IV inhibition upregulates GLUT4 translocation and expression in heart and skeletal muscle of spontaneously hypertensive rats
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DOI：
10.1016/j.ejphar.2012.09.043
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发表时间：
2013-01-05
影响因子：
5
通讯作者：
Girardi, Adriana C. C.
中科院分区：
文献类型：
--
作者：
Giannocco, Gisele;Oliveira, Kelen C.;Girardi, Adriana C. C.
本研究的目的是检验二肽基肽酶IV（DPPIV）抑制剂西格列汀（具有降糖和降压作用）上调自发性高血压大鼠（SHR）心脏和骨骼肌中GLUT 4易位、蛋白水平和/或mRNA表达的假设。西格列汀（40 mg/kg，每日两次）治疗10天，使年轻（Y，5周龄）和成年（A，20周龄）SHR的血浆DPPIV活性降低至相似程度（相似于85%）。然而，DPPIV抑制仅降低了Y-SHR的血压（119 +/- 3 vs. 136 +/- 4 mmHg）。与年龄匹配的Wistar京都（WKY）正常血压大鼠相比，SHR的心脏、比目鱼肌和腓肠肌中GLUT 4易位、总蛋白水平和mRNA表达均降低。A-SHR和A-WKY大鼠之间的这些差异比Y-SHR和Y-WKY大鼠之间的差异更明显。在Y-SHR中，西格列汀使心脏、比目鱼肌和腓肠肌中的GLUT 4表达正常化。在A-SHR中，西格列汀使GLUT 4表达增加至甚至高于A-WKY大鼠的水平。西格列汀可提高SHR中DPPIV底物胰高血糖素样肽-1（GLP-1）的循环水平。此外，刺激从SHR分离的心肌细胞中的GLP-1受体使GLUT 4的蛋白水平增加了154 +/-13%。总的来说，这些结果表明DPPIV抑制上调SHR心脏和骨骼肌中的GLUT 4。西格列汀诱导的SHR GLUT 4上调的潜在机制可能至少部分归因于GLP-1。(C)2012爱思唯尔有限公司版权所有。
The purpose of the current study was to test the hypothesis that the dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which exerts anti-hyperglycemic and anti-hypertensive effects, upregulates GLUT4 translocation, protein levels, and/or mRNA expression in heart and skeletal muscle of spontaneously hypertensive rats (SHRs). Ten days of treatment with sitagliptin (40 mg/kg twice daily) decreased plasma DPPIV activity in both young (Y, 5-week-old) and adult (A, 20-week-old) SHRs to similar extents ( similar to 85%). However, DPPIV inhibition only lowered blood pressure in Y-SHRs (119 +/- 3 vs. 136 +/- 4 mmHg). GLUT4 translocation, total protein levels and mRNA expression were decreased in the heart, soleus and gastrocnemius muscle of SHRs compared to age-matched Wistar Kyoto (WKY) normotensive rats. These differences were much more pronounced between A-SHRs and A-WKY rats than between Y-SHRs and Y-WKY rats. In Y-SHRs, sitagliptin normalized GLUT4 expression in the heart, soleus and gastrocnemius. In A-SHRs, sitagliptin increased GLUT4 expression to levels that were even higher than those of A-WKY rats. Sitagliptin enhanced the circulating levels of the DPPIV substrate glucagon-like peptide-1 (GLP-1) in SHRs. In addition, stimulation of the GLP-1 receptor in cardiomyocytes isolated from SHRs increased the protein level of GLUT4 by 154 +/- 13%. Collectively, these results indicate that DPPIV inhibition upregulates GLUT4 in heart and skeletal muscle of SHRs. The underlying mechanism of sitagliptin-induced upregulation of GLUT4 in SHRs may be, at least partially, attributed to GLP-1. (C) 2012 Elsevier B.V. All rights reserved.