title: Advanced glycation end-products impair Na⁺/K⁺-ATPase activity in diabetic cardiomyopathy: role of the adenosine monophosphate-activated protein kinase/sirtuin 1 pathway.
abstract: Decreased Na(+) /K(+) -ATPase activity, and both sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) have been reported to be involved in the development of diabetic cardiomyopathy (DCM). The present study aimed to investigate the advanced glycation end-products (AGE) that impair Na(+) /K(+) -ATPase stability by regulating the AMPK/SIRT1 pathway during progression of DCM. To study type 1 diabetic mellitus (T1DM), a disease model in rats was established by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg), and neonatal rat cardiomyocytes were also cultured. Heart function was detected by Doppler, and SIRT1 and AMPK protein expression were detected by immunohistochemistry and western blotting. Na(+) /K(+) -ATPase activity was also monitored. Using in vivo rat models of DCM, we showed that Na(+) /K(+) -ATPase activity decreased when both AMPK and SIRT1 expression were downregulated. In vitro, AGE impaired Na(+) /K(+) -ATPase activity and decreased the AMPK and SIRT1 expression. Sirtuin 1 overexpression increased Na(+) /K(+) -ATPase activity. 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) upregulated SIRT1 expression and increased Na(+) /K(+) -ATPase activity, which could be partially abolished by splitomicin. Our results suggest that the dysfunction of DCM is related to AGE-induced Na(+) /K(+) -ATPase activity impairment through a mechanism involving the AMPK/SIRT1 pathway.
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yuan
authors.forename: Qian-Yi
authors.initials: QY
authors.lastname: Zhou
authors.forename: Du
authors.initials: D
authors.lastname: Liu
authors.forename: Lun
authors.initials: L
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Zhan
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Li
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Peng
authors.forename: Xiu-Ling
authors.initials: XL
authors.lastname: Zhang
authors.forename: Xin-Chu
authors.initials: XC
authors.lastname: Yuan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D004452:Echocardiography; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism*; D006334:Heart Function Tests; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013311:Streptozocin / Q000494:pharmacology; D016277:Ventricular Function, Left
chemical_list: D017127:Glycation End Products, Advanced; D013311:Streptozocin; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Na+/K+-ATPase; adenosine monophosphate-activated protein kinase; diabetic cardiomyopathy; sirtuin 1