title: Linagliptin reduces effects of ET-1 and TLR2-mediated cerebrovascular hyperreactivity in diabetes.
abstract: OBJECTIVE
  The anti-hyperglycemic agent linagliptin, a dipeptidyl peptidase-4 inhibitor, has been shown to reduce inflammation and improve endothelial cell function. In this study, we hypothesized that DPP-IV inhibition with linagliptin would improve impaired cerebral blood flow in diabetic rats through improved insulin-induced cerebrovascular relaxation and reversal of pathological cerebrovascular remodeling that subsequently leads to improvement of cognitive function.
  
  
  METHODS
  Male type-2 diabetic Goto-Kakizaki (GK) and nondiabetic Wistar rats were treated with linagliptin, and ET-1 plasma levels and dose response curves to ET-1 (0.1-100nM) in basilar arteries were assessed. The impact of TLR2 antagonism on ET-1 mediated basilar contraction and endothelium-dependent relaxation to acetylcholine (ACh, 1nM-1M) in diabetic GK rats was examined with antibody directed against the TLR2 receptor (Santa Cruz, 5μg/mL). The expression of TLR2 in middle cerebral arteries (MCAs) from treated rats and in brain microvascular endothelial cells (BMVEC) treated with 100nM linagliptin was assessed.
  
  
  RESULTS
  Linagliptin lowered plasma ET-1 levels in diabetes, and reduced ET-1-induced vascular contraction. TLR2 antagonism in diabetic basilar arteries reduced ET-1-mediated cerebrovascular dysfunction and improved endothelium-dependent vasorelaxation. Linagliptin treatment in the BMVEC was able to reduce TLR2 expression in cells from both diabetic and nondiabetic rats.
  
  
  CONCLUSIONS
  These results suggest that inhibition of DPPIV using linagliptin improves the ET-1-mediated cerebrovascular dysfunction observed in diabetes through a reduction in ET-1 plasma levels and reduced cerebrovascular hyperreactivity. This effect is potentially a result of linagliptin causing a decrease in endothelial TLR2 expression and a subsequent increase in NO bioavailability.
authors.affiliation: Department of Physiology, Augusta University, Augusta, GA, United States.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hardigan
authors.affiliation: Department of Physiology, Augusta University, Augusta, GA, United States.
authors.forename: Yasir
authors.initials: Y
authors.lastname: Abdul
authors.affiliation: Department of Physiology, Augusta University, Augusta, GA, United States; Charlie Norwood Veterans Administration Medical Center, Augusta, GA, United States. Electronic address: aergul@gru.edu.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D019332:Endothelin-1 / Q000097:blood / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069476:Linagliptin / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D019332:Endothelin-1; D007004:Hypoglycemic Agents; C495343:Tlr2 protein, rat; D051195:Toll-Like Receptor 2; D000069476:Linagliptin
keywords: Cerebrovasculature; Diabetes; Endothelin; Linagliptin; TLR2