{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T08:43:57Z","timestamp":1768034637337,"version":"3.49.0"},"reference-count":56,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,5,27]],"date-time":"2014-05-27T00:00:00Z","timestamp":1401148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2014,6]]},"abstract":"Background and Purpose<\/jats:title>PPAR\u03b2 enhances insulin sensitivity in adipocytes and skeletal muscle cells, but its effects on insulin signalling in endothelial cells are not known. We analysed the effects of the PPAR<\/jats:styled-content>\u03b2\/\u03b4 (PPAR<\/jats:styled-content>\u03b2) agonists, GW<\/jats:styled-content>0742 and L<\/jats:styled-content>165041, on impaired insulin signalling induced by high glucose in HUVECs<\/jats:styled-content> and aortic and mesenteric arteries from diabetic rats.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>Insulin\u2010stimulated NO<\/jats:styled-content> production, Akt<\/jats:styled-content>\u2010Ser<\/jats:styled-content>473<\/jats:sup> and eNOS<\/jats:styled-content>\u2010Ser<\/jats:styled-content>1177<\/jats:sup> phosphorylation, and reactive oxygen species (ROS<\/jats:styled-content>) production were studied in HUVECs<\/jats:styled-content> incubated in low\u2010 or high\u2010glucose medium. Insulin\u2010stimulated relaxations and protein phosphorylation in vessels from streptozotocin (STZ<\/jats:styled-content>)\u2010induced diabetic rats were also analysed.<\/jats:p><\/jats:sec>Key Results<\/jats:title>HUVECs<\/jats:styled-content> incubated in high\u2010glucose medium showed a significant reduction in insulin\u2010stimulated production of NO<\/jats:styled-content>. High glucose also reduced insulin\u2010induced Akt<\/jats:styled-content>\u2010Ser<\/jats:styled-content>473<\/jats:sup> and eNOS<\/jats:styled-content>\u2010Ser<\/jats:styled-content>1177<\/jats:sup> phosphorylation, increased IRS<\/jats:styled-content>\u20101\u2010Ser636<\/jats:sup> and ERK<\/jats:styled-content>1\/2\u2010Thr<\/jats:styled-content>183<\/jats:sup>\u2010Tyr<\/jats:styled-content>185<\/jats:sup> phosphorylation and increased ROS<\/jats:styled-content> production. The co\u2010incubation with the PPAR<\/jats:styled-content>\u03b2 agonists GW<\/jats:styled-content>0742 or L<\/jats:styled-content>165041 prevented all these effects induced by high glucose. In turn, the effects induced by the agonists were suppressed when HUVEC<\/jats:styled-content> were also incubated with the PPAR<\/jats:styled-content>\u03b2 antagonist GSK<\/jats:styled-content>0660, the pyruvate dehydrogenase kinase (PDK<\/jats:styled-content>)4 inhibitor dichloroacetate or after knockdown of both PPAR<\/jats:styled-content>\u03b2 and PDK<\/jats:styled-content>4 with siRNA<\/jats:styled-content>. The ERK<\/jats:styled-content>1\/2 inhibitor PD<\/jats:styled-content>98059, ROS<\/jats:styled-content> scavenger catalase, inhibitor of complex II<\/jats:styled-content> thenoyltrifluoroacetone or uncoupler of oxidative phosphorylation, carbonyl cyanide m\u2010chlorophenylhydrazone, also prevented glucose\u2010induced insulin resistance. In STZ<\/jats:styled-content> diabetic rats, oral GW<\/jats:styled-content>0742 also improved insulin signalling and the impaired NO<\/jats:styled-content>\u2010mediated vascular relaxation.<\/jats:p><\/jats:sec>Conclusion and Implications<\/jats:title>PPAR<\/jats:styled-content>\u03b2 activation in vitro<\/jats:italic> and in vivo<\/jats:italic> restores the endothelial function, preserving the insulin\u2010Akt<\/jats:styled-content>\u2010eNOS<\/jats:styled-content> pathway impaired by high glucose, at least in part, through PDK<\/jats:styled-content>4 activation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12646","type":"journal-article","created":{"date-parts":[[2014,2,17]],"date-time":"2014-02-17T11:43:17Z","timestamp":1392637397000},"page":"3089-3102","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["PPAR<\/scp>\u03b2 activation restores the high glucose\u2010induced impairment of insulin signalling in endothelial cells"],"prefix":"10.1111","volume":"171","author":[{"given":"A M","family":"Quintela","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Granada 18071 Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Granada 18071 Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Piqueras","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Valencia Valencia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"G\u00f3mez\u2010Guzm\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Granada 18071 Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Haro","sequence":"additional","affiliation":[{"name":"Service of Gynecology Clinic Hospital of Granada Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M J","family":"Zarzuelo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Granada 18071 Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Cogolludo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Medicine University Complutense of Madrid IdISSC and Ciber Enfermedades Respiratorias (CIBERES) Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M J","family":"Sanz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Valencia Valencia 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