Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats

被引:79
作者
Al-Rasheed, Nouf M. [1 ]
Al-Rasheed, Nawal M. [1 ,2 ]
Hasan, Iman H. [1 ]
Al-Amin, Maha A. [1 ]
Al-Ajmi, Hanaa N. [1 ]
Mahmoud, Ayman M. [3 ]
机构
[1] King Saud Univ, Coll Pharm, Dept Pharmacol & Toxicol, Riyadh, Saudi Arabia
[2] Princess Nourah Bint Abdulrahman Univ, Coll Pharm, Dept Pharmaceut Sci, Riyadh, Saudi Arabia
[3] Beni Suef Univ, Fac Sci, Div Physiol, Dept Zool, Bani Suwayf 62514, Egypt
来源
DRUG DESIGN DEVELOPMENT AND THERAPY | 2016年 / 10卷
关键词
diabetic cardiomyopathy; DPP-4; inhibitors; JAK/STAT; oxidative stress; inflammation; GLUCAGON-LIKE PEPTIDE-1; NITRIC-OXIDE SYNTHASE; OXIDATIVE STRESS; HEART-FAILURE; DIASTOLIC DYSFUNCTION; CARDIAC-HYPERTROPHY; BLOOD-PRESSURE; FIBROSIS; INFLAMMATION; BIOLOGY;
D O I
10.2147/DDDT.S109287
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has been reported to promote cardioprotection in diabetic hearts by limiting hyperglycemia and hyperlipidemia. However, little is known about the involvement of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway modulation in the cardioprotective effects of sitagliptin. The current study aimed to investigate the protective effects of sitagliptin against diabetic cardiomyopathy (DCM), focusing on the modulation of the JAK/STAT pathway. Diabetes was induced by streptozotocin injection, and rats received sitagliptin orally and daily for 90 days. Diabetic rats exhibited hyperglycemia, hyperlipidemia, and a significant increase in heart-to-body weight (HW/BW) ratio. Serum troponin I and creatine kinase MB, cardiac interleukin-6 (IL-6), lipid peroxidation, and nitric oxide levels showed significant increase in diabetic rats. In contrast, both enzymatic and nonenzymatic antioxidant defenses were significantly declined in the heart of diabetic rats. Histopathological study revealed degenerations, increased collagen deposition in the heart of diabetic rats. Sitagliptin alleviated hyperglycemia, hyperlipidemia, HW/BW ratio, histological architecture, oxidative stress, and inflammation, and rejuvenated the antioxidant defenses. In addition, cardiac levels of pJAK2 and pSTAT3 were increased in diabetic rats, an effect which was remarkably decreased after sitagliptin treatment. In conclusion, these results confer an evidence that sitagliptin has great therapeutic potential on DCM through down-regulation of the JAK/STAT signaling pathway.
引用
收藏
页码:2095 / 2107
页数:13
相关论文
共 62 条
[31]   Parkinsonia aculeata aqueous extract fraction: Biochemical studies in alloxan-induced diabetic rats [J].
Leite, A. C. R. ;
Araujo, T. G. ;
Carvalho, B. M. ;
Silva, N. H. ;
Lima, V. L. M. ;
Maia, M. B. S. .
JOURNAL OF ETHNOPHARMACOLOGY, 2007, 111 (03) :547-552
[32]   18β-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity: potential role of PPARγ and Nrf2 upregulation [J].
Mahmoud, Ayman M. ;
Al Dera, Hussein S. .
GENES AND NUTRITION, 2015, 10 (06)
[33]   Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats [J].
Mahmoud, Ayman M. ;
Ashour, Mohamed B. ;
Abdel-Moneim, Adel ;
Ahmed, Osama M. .
JOURNAL OF DIABETES AND ITS COMPLICATIONS, 2012, 26 (06) :483-490
[34]  
MARKLUND S, 1974, EUR J BIOCHEM, V47, P469
[35]   DIRECT STIMULATION OF JAK/STAT PATHWAY BY THE ANGIOTENSIN-II AT(1) RECEPTOR [J].
MARRERO, MB ;
SCHIEFFER, B ;
PAXTON, WG ;
HEERDT, L ;
BERK, BC ;
DELAFONTAINE, P ;
BERNSTEIN, KE .
NATURE, 1995, 375 (6528) :247-250
[36]   TGF-β signal transduction [J].
Massagué, J .
ANNUAL REVIEW OF BIOCHEMISTRY, 1998, 67 :753-791
[37]  
McCann FJ, 2012, PLOS ONE, V7, DOI [10.1371/journal.pone.0049894, 10.1371/journal.pone.0052013]
[38]   Inducible nitric oxide synthase is required in alcohol-induced liver injury:: Studies with knockout mice [J].
McKim, SE ;
Gäbele, E ;
Isayama, F ;
Lambert, JC ;
Tucker, LM ;
Wheeler, MD ;
Connor, HD ;
Mason, RP ;
Doll, MA ;
Hein, DW ;
Arteel, GE .
GASTROENTEROLOGY, 2003, 125 (06) :1834-1844
[39]   Diminished glucagon suppression after β-cell reduction is due to impaired α-cell function rather than an expansion of α-cell mass [J].
Meier, Juris J. ;
Ueberberg, Sandra ;
Korbas, Simone ;
Schneider, Stephan .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2011, 300 (04) :E717-E723
[40]  
MONTGOMERY H, 1961, ANALYST, V86, P414