title: Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system.
abstract: BACKGROUND
  Endothelin-1 (ET-1) mediates cerebrovascular remodeling in vascular smooth muscle layer of the middle cerebral arteries (MCA) in type-2 diabetic Goto-Kakizaki (GK) rats. While metformin, oral glucose lowering agent, prevent/restores vascular remodeling and reduce systemic and local ET-1 levels whether this effect was specific to metformin remained unknown. Our working hypotheses were 1) linagliptin, a DPP-IV inhibitor, can reverse diabetes-mediated cerebrovascular remodeling and this is associated with decreased ET-1, and 2) linagliptin prevents the high glucose induced increase in ET-1 and ET receptors in brain vascular smooth muscle cells (bVSMCs).
  
  
  METHODS
  Diabetic and non-diabetic GK rats were treated with linagliptin (4weeks). MCAs were fixed in buffered 4% paraformaldehyde and used for morphometry. Human bVSMCs incubated in normal glucose (5.5mM)/high glucose (25mM) conditions were treated with the linagliptin (100nM; 24h). ET-1 secretion and ET receptors were measured in media and cell lysate respectively. Immunostaining was performed for ET-A and ET-B receptor. ET receptors were also measured in cells treated with ET-1 (100nM) and linagliptin.
  
  
  RESULTS
  Linagliptin treatment regressed vascular remodeling of MCAs in diabetic animals but had no effect on blood glucose. bVSMCs in normal/high glucose condition did not show any significant difference in ET-1 secretion or ET-A and ET-B receptor expression. ET-1 treatment in high glucose condition significantly increased the ET-A receptors and this effect was inhibited by linagliptin.
  
  
  CONCLUSIONS
  Linagliptin is effective in reversing established pathological cerebrovascular remodeling associated with diabetes. Attenuation of the ET system could be a pleiotropic effect of linagliptin that provides vascular protection.
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta University, Augusta, Georgia, United States; Department of Physiology, Augusta University, Augusta, Georgia, United States.
authors.forename: Abdul
authors.initials: A
authors.lastname: Yasir
authors.affiliation: Department of Physiology, Augusta University, Augusta, Georgia, United States.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hardigan
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta University, Augusta, Georgia, United States; Department of Physiology, Augusta University, Augusta, Georgia, United States. Electronic address: aergul@gru.edu.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D019332:Endothelin-1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069476:Linagliptin / Q000494:pharmacology*; D008297:Male; D020768:Middle Cerebral Artery / Q000473:pathology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D005947:Glucose
keywords: Diabetes; Endothelin; Linagliptin and brain vascular smooth muscle cells