PMID- 28899902 OWN - NLM STAT- MEDLINE DCOM- 20171010 LR - 20220129 IS - 1470-8736 (Electronic) IS - 0143-5221 (Print) IS - 0143-5221 (Linking) VI - 131 IP - 20 DP - 2017 Oct 1 TI - Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR(-/-) mouse model of atherosclerosis. PG - 2489-2501 LID - 10.1042/CS20171066 [doi] AB - 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 an 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 by 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 AMPKalpha. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk. CI - (c) 2017 The Author(s). FAU - Thompson, Dawn AU - Thompson D AD - School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, U.K. m.delibegovic@abdn.ac.uk dthompson@abdn.ac.uk. FAU - Morrice, Nicola AU - Morrice N AD - School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, U.K. FAU - Grant, Louise AU - Grant L AD - School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, U.K. FAU - Le Sommer, Samantha AU - Le Sommer S AD - School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, U.K. FAU - Lees, Emma K AU - Lees EK AD - School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, U.K. FAU - Mody, Nimesh AU - Mody N AD - School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, U.K. FAU - Wilson, Heather M AU - Wilson HM AD - School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, U.K. FAU - Delibegovic, Mirela AU - Delibegovic M AD - School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, U.K. m.delibegovic@abdn.ac.uk dthompson@abdn.ac.uk. LA - eng GR - PG/11/8/28703/BHF_/British Heart Foundation/United Kingdom GR - PG/14/43/30889/BHF_/British Heart Foundation/United Kingdom PT - Journal Article DEP - 20170928 PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - 0 (3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate) RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Cholestanes) RN - 0 (Enzyme Inhibitors) RN - 0 (Receptors, LDL) RN - 0 (Triglycerides) RN - 2FZ7Y3VOQX (Spermine) RN - 97C5T2UQ7J (Cholesterol) RN - EC 2.7.11.1 (AMPK alpha1 subunit, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1) RN - EC 3.1.3.48 (Ptpn1 protein, mouse) SB - IM CIN - Clin Sci (Lond). 2018 Jan 2;132(1):37-38. PMID: 29295951 CIN - Clin Sci (Lond). 2018 Jan 2;132(1):39-41. PMID: 29295952 MH - AMP-Activated Protein Kinases/metabolism MH - Animals MH - Aorta/*drug effects/enzymology/pathology MH - Aortic Diseases/enzymology/genetics/pathology/*prevention & control MH - Atherosclerosis/enzymology/genetics/pathology/*prevention & control MH - Biomarkers/blood MH - Blood Glucose/drug effects/metabolism MH - Chemokine CCL2/metabolism MH - Cholestanes/*administration & dosage MH - Cholesterol/blood MH - Diet, High-Fat MH - Disease Models, Animal MH - Drug Administration Schedule MH - Enzyme Inhibitors/*administration & dosage MH - Genetic Predisposition to Disease MH - Homeostasis MH - Male MH - Mice, Knockout MH - Phenotype MH - Phosphorylation MH - *Plaque, Atherosclerotic MH - Protein Tyrosine Phosphatase, Non-Receptor Type 1/*antagonists & inhibitors/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Receptors, LDL/*deficiency/genetics MH - Signal Transduction/drug effects MH - Spermine/administration & dosage/*analogs & derivatives MH - Time Factors MH - Triglycerides/blood MH - Weight Loss PMC - PMC6365594 OTO - NOTNLM OT - atherosclerosis OT - metabolic syndromes OT - protein tyrosine phosphatases COIS- The authors declare that there are no competing interests associated with the manuscript. EDAT- 2017/09/14 06:00 MHDA- 2017/10/11 06:00 PMCR- 2017/09/29 CRDT- 2017/09/14 06:00 PHST- 2017/05/24 00:00 [received] PHST- 2017/09/04 00:00 [revised] PHST- 2017/09/06 00:00 [accepted] PHST- 2017/09/14 06:00 [pubmed] PHST- 2017/10/11 06:00 [medline] PHST- 2017/09/14 06:00 [entrez] PHST- 2017/09/29 00:00 [pmc-release] AID - CS20171066 [pii] AID - 10.1042/CS20171066 [doi] PST - epublish SO - Clin Sci (Lond). 2017 Sep 28;131(20):2489-2501. doi: 10.1042/CS20171066. Print 2017 Oct 1.