Pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis

Dawn Thompson, Nicola Morrice, Louise Grant, Samantha Le Sommer, Emma K Lees, Nimesh Mody, Heather M Wilson, Mirela Delibegovic

Research output: Contribution to journalArticle

9 Citations (Scopus)
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Abstract

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in LDLR-/- mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR-/- mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied with a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels, and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction of CVD risk.
Original languageEnglish
Pages (from-to)2489-2501
Number of pages13
JournalClinical Science
Volume131
Issue number20
Early online date12 Sep 2017
DOIs
Publication statusPublished - 29 Sep 2017

Keywords

  • insulin
  • insulin resistance
  • insulin receptor
  • AMPK
  • atherosclerosis

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