title: Protective effects of sitagliptin on myocardial injury and cardiac function in an ischemia/reperfusion rat model.
abstract: The purpose of this study is to investigate the effects and the underlying mechanisms of sitagliptin pretreatment on myocardial injury and cardiac function in myocardial ischemia/reperfusion (I/R) rat model. The rat model of myocardial I/R was constructed by coronary occlusion. Rats were pretreated with sitagliptin (300 mg/kg/day) for 2 weeks, and then subjected to 30 min ischemia and 2h reperfusion. The release of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB), cardiac function and cardiomyocyte apoptosis were evaluated. The levels of malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in heart and glucagon-like peptide-1 (GLP-1) level in plasma were measured. Western blot analysis was performed to detect the target proteins of sitagliptin. Our results showed that sitagliptin pretreatment decreased LDH and CK-MB release, and MDA level in I/R rats. More importantly, we revealed for the first time that sitagliptin pretreatment decreased cardiomyocyte apoptosis while increased the levels of GSH-Px and SOD in heart. Sitagliptin also increased GLP-1 level and enhanced cardiac function in I/R rats. Furthermore, sitagliptin pretreatment up-regulated Akt(serine473) and Bad(serine136) phosphorylation, reduced the ratio of Bax/Bcl-2, and decreased expression levels of cleaved caspase-3 and caspase-3. Interestingly, the above observed effects of sitagliptin were all abolished when co-administered with GLP-1 receptor antagonist exendin-(9-39) or PI3K inhibitor LY294002. Taken together, our data indicate that sitagliptin pretreatment could reduce myocardial injury and improve cardiac function in I/R rats by reducing apoptosis and oxidative damage. The underlying mechanism might be the activation of PI3K/Akt signaling pathway by GLP-1/GLP-1 receptor.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, PR China.
authors.forename: Guanglei
authors.initials: G
authors.lastname: Chang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Ye
authors.forename: Kai
authors.initials: K
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Qin
authors.initials: Q
authors.lastname: Duan
authors.forename: Aihua
authors.initials: A
authors.lastname: Zheng
authors.forename: Shu
authors.initials: S
authors.lastname: Qin
authors.forename: Dongying
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D052279:Creatine Kinase, MB Form / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000097:blood / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D000068900:Sitagliptin Phosphate; D013482:Superoxide Dismutase / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D011719:Pyrazines; D018027:Receptors, Glucagon; D014230:Triazoles; D008315:Malondialdehyde; D052216:Glucagon-Like Peptide 1; D007770:L-Lactate Dehydrogenase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D052279:Creatine Kinase, MB Form; D005947:Glucose; D000068900:Sitagliptin Phosphate
keywords: Cardiac function; Cardiomyocyte apoptosis; DPP4 inhibitor; Ischemia/reperfusion; Myocardial injury; Sitagliptin