Letter by Krötz et al Regarding Article, “Improvement of Peripheral Endothelial Dysfunction by Protein Tyrosine Phosphatase Inhibitors in Heart Failure”
To the Editor:
In their article “Improvement of Peripheral Endothelial Dysfunction by Protein Tyrosine Phosphatase Inhibitors in Heart Failure,” Vercauteren et al1 observed beneficial effects of protein tyrosine phosphatase 1B (PTP1b) inhibition on acetylcholine-mediated, NO-dependent, peripheral arterial vasodilation. They conclude that PTP1b inhibition may be a potent treatment for endothelial dysfunction in chronic heart failure, as it favors tyrosine phosphorylation and may thus restore altered endothelial NO production.
Indeed, inhibitors of PTP1b may have great potential for vascular medicine because of their antidiabetic effects. However, preservation of tyrosine phosphorylation as a therapeutic principle for vascular medicine must be viewed in a more differentiated manner, as the cellular effects and functions of the numerous different cytosolic and membrane-bound tyrosine phosphatases are multiple and many times antagonistic.2 Nonspecific protein tyrosine phosphatase inhibitors, such as orthovanadate, also have detrimental effects on vascular function (eg, by enhanced production of vascular reactive oxygen species).3 We have demonstrated that inactivation of the cytosolic tyrosine phosphatase SHP-1, which is also nonspecifically inhibited by some of the PTP1b inhibitors used by Vercauteren et al,4 potentiates endothelial reactive oxygen species production. In addition, the involvement of the SHP-2 isoform in endothelial NO synthase activation is probably not related to its phosphatase activity but to the function of SHP-2 as an adapter molecule.5
Use of pharmacological inhibitors as therapeutic agents, especially in the case of tyrosine phosphatases, where nonspecific effects on structurally closely related enzymes may be related with severe and unpredictable side effects, thus should be performed with great caution.2 We agree with Vercauteren et al that interference with tyrosine phosphatase signaling in vascular biology has great therapeutic potential. We suggest that small molecule approaches, such as the use of small interfering RNAs or antisense-desoxynucleotides, might provide a more useful approach for the development of highly specific phosphatase inhibitors for vascular medicine.
Vercauteren M, Remy E, Devaux C, Dautreaux B, Henry JP, Bauer F, Mulder P, Hooft van Huijsduijnen R, Bombrun A, Thuillez C, Richard V. Improvement of peripheral endothelial dysfunction by protein tyrosine phosphatase inhibitors in heart failure. Circulation. 2006; 114: 2498–2507.
Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: part II: animal and human studies. Circulation. 2003; 108: 2034–2040.
Dixit M, Loot AE, Mohamed A, Fisslthaler B, Boulanger CM, Ceacareanu B, Hassid A, Busse R, Fleming I. Gab1, SHP2, and protein kinase A are crucial for the activation of the endothelial NO synthase by fluid shear stress. Circ Res. 2005; 97: 1236–1244.