Published Online
on November 13, 2006

A more recent version of this article appeared on December 5, 2006

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Submitted on March 29, 2006
Revised on September 22, 2006
Accepted on September 29, 2006

Improvement of Peripheral Endothelial Dysfunction by Protein Tyrosine Phosphatase Inhibitors in Heart Failure

Magali Vercauteren BSc, Elise Remy PharmD, Corinne Devaux PhD, Brigitte Dautreaux BSc, Jean-Paul Henry BSc, Fabrice Bauer MD, Paul Mulder PhD, Rob Hooft van Huijsduijnen PhD, Agnès Bombrun PhD, Christian Thuillez MD, PhD, and Vincent Richard PhD^*

From INSERM U644, Federate Institute for Multidisciplinary Research on Peptides, Rouen University Medical School, Rouen, France (M.V., E.R., C.D., B.D., J.H., F.B., P.M., C.T., V.R.); and Serono Pharmaceutical Research Institute, Geneva, Switzerland (R.H.v.H., A.B.).

^* To whom correspondence should be addressed. E-mail: Vincent.Richard{at}univ-rouen.fr.

Background--Chronic heart failure (CHF) induces endothelial dysfunction characterized by a decrease in nitric oxide (NO) production in response to flow (flow-mediated dilatation [FMD]). Because activation of endothelial NO synthase (eNOS) by flow requires tyrosine phosphorylation, we tested whether endothelial dysfunction could be corrected by increasing phosphotyrosine levels using protein tyrosine phosphatase (PTP) inhibitors and especially inhibitors of PTP1B.

Methods and Results--CHF was induced by coronary ligation in mice, and FMD was assessed in isolated and cannulated mesenteric artery segments (2 mm in length and <300 µm in diameter). CHF almost abolished FMD but only moderately affected the response to acetylcholine. In mice with CHF, the PTP1B inhibitors AS279, AS098, and AS713 restored FMD to levels similar to those of normal mice. This restoration was reduced by inhibitors of eNOS and phosphatidylinositol-3 kinase. Polymerase chain reaction and Western blot showed that arteries express PTP1B, and this expression was not affected by CHF. Immunolocalization revealed the presence of PTP1B in the endothelium and the adventitia. Flow induced a transient eNOS phosphorylation that was absent in CHF. PTP1B inhibition stimulated early eNOS phosphorylation and increased phosphorylation of Akt.

Conclusions--Our results demonstrate for the first time that PTP1B inhibitors may be potent treatments for endothelial dysfunction.

Key words: acetylcholine • blood flow • echocardiography • endothelium • endothelium-derived factors • heart failure • signal transduction

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