Linagliptin reduces effects of ET-1 and TLR2-mediated cerebrovascular hyperreactivity in diabetes

Trevor Hardigan, Yasir Abdul, Adviye Ergul

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Aims 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. Main 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 (0.1–100 nM) in basilar arteries were assessed. The impact of TLR2 antagonism on ET-1 mediated basilar contraction and endothelium-dependent relaxation to acetylcholine (ACh, 1 nM–1 M) in diabetic GK rats was examined with antibody directed against the TLR2 receptor (Santa Cruz, 5 μg/mL). The expression of TLR2 in middle cerebral arteries (MCAs) from treated rats and in brain microvascular endothelial cells (BMVEC) treated with 100 nM linagliptin was assessed. Key findings 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.

Original languageEnglish (US)
Pages (from-to)90-96
Number of pages7
JournalLife sciences
Volume159
DOIs
StatePublished - Aug 15 2016

Fingerprint

Medical problems
Rats
Endothelial cells
Basilar Artery
Endothelial Cells
Plasmas
Endothelium
Brain
Cerebrovascular Circulation
Dipeptidyl-Peptidase IV Inhibitors
Toll-Like Receptor 2
Linagliptin
Middle Cerebral Artery
Vasodilation
Cognition
Biological Availability
Acetylcholine
Blood Vessels
Wistar Rats
Blood

Keywords

  • Cerebrovasculature
  • Diabetes
  • Endothelin
  • Linagliptin
  • TLR2

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Linagliptin reduces effects of ET-1 and TLR2-mediated cerebrovascular hyperreactivity in diabetes. / Hardigan, Trevor; Abdul, Yasir; Ergul, Adviye.

In: Life sciences, Vol. 159, 15.08.2016, p. 90-96.

Research output: Contribution to journalArticle

Hardigan, Trevor ; Abdul, Yasir ; Ergul, Adviye. / Linagliptin reduces effects of ET-1 and TLR2-mediated cerebrovascular hyperreactivity in diabetes. In: Life sciences. 2016 ; Vol. 159. pp. 90-96.
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