Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B.

Abstract : Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF). We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure.
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Journal of Molecular and Cellular Cardiology, Elsevier, 2012, 52 (6), pp.1257-64. 〈10.1016/j.yjmcc.2012.03.003〉
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Soumis le : vendredi 15 mars 2013 - 15:03:42
Dernière modification le : mardi 5 juin 2018 - 10:14:35

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Elodie Gomez, Magali Vercauteren, Baptiste Kurtz, Antoine Ouvrard-Pascaud, Paul Mulder, et al.. Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B.. Journal of Molecular and Cellular Cardiology, Elsevier, 2012, 52 (6), pp.1257-64. 〈10.1016/j.yjmcc.2012.03.003〉. 〈inserm-00801304〉

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