title: Urocortin attenuates myocardial fibrosis in diabetic rats via the Akt/GSK-3β signaling pathway.
abstract: OBJECTIVE
  Urocortin, a novel identified corticotropin-releasing factor-related endocrinal peptide, has been shown to play an essential role in cardioprotection. Until recently, whether urocortin can protect the heart against diabetic cardiomyopathy (DCM) remained unclear. Herein, we evaluated the cardioprotective effect of urocortin on cardiac dysfunction, inflammation, and fibrosis and demonstrated the potential mechanism in a diabetic rat model.
  
  
  METHODS
  Diabetic rats were randomly divided into 4 groups: diabetic control group, urocortin, urocortin + astressin (a selective CRF receptor 2 antagonist) and urocortin + triciribine (an Akt pathway blocker). Cardiac catheterization was performed to evaluate cardiac function. The levels of creatine phosphokinase isoenzyme (CK-MB), plasma brain natriuretic peptide (BNP), myocardial collagen volume fraction (CVF) and left ventricular mass index (LVWI) were measured. Inflammatory factors (transforming growth factor beta 1, TGF-β1; connective tissue growth factor, CTGF) and activation of signaling proteins (Akt, GSK-3β) were also detected using western blot.
  
  
  RESULTS
  DCM was successfully induced by the injection of streptozotocin (STZ) as evidenced by abnormal heart mass and cardiac function as well as the imbalance of extracellular matrix homeostasis. Rats in the DCM group showed increased mRNA and protein levels of LVWI, BNP, CK-MB, CVF, TGF-β1 and CTGF compared to the control group, which were accompanied with diminished phosphorylation of Akt and GSK-3β. Interestingly, myocardial dysfunction, cardiac fibrosis, and inflammation were suppressed by urocortin in the heart of diabetic rats. Moreover, inhibition of phosphorylation of Akt and GSK-3β was also reversed by urocortin. These effects of urocortin were suppressed by astressin. In addition, triciribine partially reduced the effects of urocortin on myocardial dysfunction, inflammation, and cardiac fibrosis.
  
  
  CONCLUSIONS
  These results suggest that urocortin exhibits a therapeutic benefit in the treatment of DCM by attenuating fibrosis and inflammation. Furthermore, inhibition of the Akt/GSK-3β signaling pathway may be partially responsible for these effects.
authors.affiliation: a The First Affiliated Hospital of Liaoning Medical University , Jinzhou , China.|b Department of Endocrinology , Provincial Hospital Affiliated to Shandong University , Jinan , China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: c Department of Pharmacology , Liaoning Medical University , Jinzhou , China.
authors.forename: Chunna
authors.initials: C
authors.lastname: Liu
authors.affiliation: a The First Affiliated Hospital of Liaoning Medical University , Jinzhou , China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: a The First Affiliated Hospital of Liaoning Medical University , Jinzhou , China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: a The First Affiliated Hospital of Liaoning Medical University , Jinzhou , China.
authors.forename: Feiran
authors.initials: F
authors.lastname: Song
authors.affiliation: b Department of Endocrinology , Provincial Hospital Affiliated to Shandong University , Jinan , China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology; D005355:Fibrosis / Q000188:drug therapy; D000071679:Glycogen Synthase Kinase 3 beta / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012263:Ribonucleosides / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D054832:Urocortins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D010446:Peptide Fragments; D012263:Ribonucleosides; D054832:Urocortins; C104416:astressin; C023764:triciribine; D003346:Corticotropin-Releasing Hormone; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: Myocardial fibrosis; corticotrophine releasing hormone; dilatetes; mellitus; transforming growth factor beta 1; urocortin