Response to Letter Regarding Article, “Improvement of Peripheral Endothelial Dysfunction by Protein Tyrosine Phosphatase Inhibitors in Heart Failure”
We thank Dr Krotz and colleagues for the comments regarding our publication1 in which they suggest that inhibitors of PTP1b may be potential treatments of endothelial dysfunction in cardiovascular diseases.1
First of all we would like to stress that, unlike what is mentioned in the first paragraph of the letter by Krotz et al, we have not observed an improvement of acetylcholine-mediated vasodilatation, which is in fact very little affected in these conditions, but essentially concentrated on the response to flow (shear stress). We believe that this difference is critical, because shear stress is likely to be the most important stimulus for NO release in physiological conditions (unlike acetylcholine), but also because many studies have clearly shown that tyrosine phosphorylation is essential for shear stress–mediated production of NO.2,3
With regard to the possible interactions with SHPs, in our experiments we found no functional evidence that the beneficial effect of the inhibitors tested were counteracted by decreased NO bioavailability secondary to increased oxidative stress. Although this does not rule out the hypothesis that these compounds increase superoxide production,4 it appears that the net effect is largely in favor of the increased NO production they induce. However, we agree that one needs to pay special attention to these potential effects on oxidative stress, especially in the context of chronic treatments. We would like to point out, however, that some of the inhibitors used (especially AS713) had no detectable inhibitory effect on SHP-1 at the concentrations used and only moderately inhibited SHP-2, and might be ideal candidates to avoid the possible unwanted effects of inhibition of SHP-1 (eg, increased oxidative stress)4 or SHP-2 (eg, altered shear stress–mediated NO production).5 Also, we could not find any evidence in reference 3 cited by Krotz et al, that “nonspecific protein tyrosine phosphatase inhibitors, such as orthovanadate, also have detrimental effects on vascular function”, but we agree with Dr Krotz and colleagues that these nonspecific inhibitors, such as orthovanadate, have little therapeutic potential in the context of vascular protection.
Finally, we agree that although our results argue for a new approach of endothelial protection, many additional steps are required to fully validate this concept and translate it into vascular medicine. As stated by Krotz et al, better selectivity may be obtained by the use of antisense desoxynucleotides or small interfering RNAs, which we in fact currently develop for PTP1b; however, at present the transfer of these laboratory approaches into clinical medicine is still very limited especially in chronic diseases, which still mostly rely on the use of “classic” pharmacological inhibitors.
Drs Hooft van Huijsduijnen and Bombrun are employees of Serono Pharmaceuticals Research Institute. Drs Richard and Thuillez have received research grants from Serono. The other authors have no conflicts of interest.
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.
Ayajiki C, Kindermann M, Hecker M, Fleming I, Busse R. Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells. Circ Res. 1996; 78: 750–775.
Fleming I, Bauersachs J, Fisslthaler B, Busse R. Ca2+-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress. Circ Res. 1998; 82: 686–695.
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.