title: Ghrelin ameliorates impaired angiogenesis of ischemic myocardium through GHSR1a-mediated AMPK/eNOS signal pathway in diabetic rats.
abstract: OBJECTIVE
  Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHSR), has been found to stimulate angiogenesis in vivo and in vitro. However, the effect and the corresponding mechanisms of ghrelin on impaired myocardial angiogenesis in diabetic and myocardial infarction (MI) rat model are still unknown.
  
  
  METHODS
  In the present study, adult SD rats were randomly divided into 4 groups: control, DM, DM+ghrelin, DM+ghrelin+[D-Lys3]-GHRP-6 groups. DM was induced by streptozotocin (STZ) 60 mg/kg body weight. 12 weeks post STZ injection all groups were subjected to MI, which was induced by ligation left anterior descending artery (LAD). Ghrelin and [D-Lys3]-GHRP-6 were administered via intraperitoneal injection at the doses 200 μg/kg and 50mg/kg for 4 weeks, respectively. Left ventricular function, microvascular density (MVD), myocardial infarct size, the expression of hypoxia-inducible factor (HIF1α), vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-1 (Flt-1), AMPK and endothelial nitric oxide synthase (eNOS) phosphorylation were examined.
  
  
  RESULTS
  Compared with the DM group, left ventricular ejection fraction (LVEF), fractional shortening (FS), and MVD were increased, whereas myocardial infarct size decreased remarkably in DM+ghrelin group. For the mechanism study, we found that ghrelin promoted the HIF1α, VEGF, Flk-1 and Flt-1 expression, AMPK and eNOS phosphorylation in diabetic rats. However, the above biochemical events in ghrelin treated diabetic rats were completely inhibited by GHSR-1a blocker [D-Lys3]-GHRP-6.
  
  
  CONCLUSIONS
  These results suggest that administration of ghrelin ameliorates impaired angiogenesis in diabetic MI rats. And these beneficial effects derive from regulating GHSR1a-mediated AMPK/eNOS signal pathway by upregulating of HIF1α, VEGF and its receptors Flk-1, Flt-1 expressions.
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China. Electronic address: chenqwcq@163.com.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Guiqiong
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Ke
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D054439:Ghrelin / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D054439:Ghrelin; C571124:Ghsr1a protein, rat; D054440:Receptors, Ghrelin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D055372:AMP-Activated Protein Kinases
keywords: Angiogenesis; Diabetes; GHSR; Ghrelin; Myocardial infarction