Resveratrol and Shp2

Cardiovascular disease is the leading cause of death in the western world. One major molecular player in the development of cardiovascular disease is angiotensin II (Ang II). It promotes growth and migration of vascular smooth muscle cells (VSMC), vascular oxidative stress and the production of growth factors and pro-inflammatory cytokines by VSMC. Ang II thereby contributes to the development of vascular damage associated with atherosclerosis, hypertension, vasculitis and diabetes. We have recently shown that resveratrol, a natural stilbene derivative, found in wines and thought to harbour major health benefits, inhibits Ang II-induced VSMC hypertrophy by interfering with the phosphatidylinositol-3-kinase (PI3 K)/Akt pathway. Seeking the molecular target of resveratrol we identified the protein tyrosine phosphatase (PTP) Shp2. Shp2 is activated by resveratrol and active Shp2 clears phospho-binding sites for the regulatory subunit p85 of PI 3 K on the adapter molecule Gab1, thus, interrupting further signalling to the PI 3 K/Akt pathway. The scientific challenges emerging from these data are (i) to clarify how resveratrol actvates the protein tyrosine phosphatase Shp2, and (ii) to show whether Shp2 may be in general a suitable and safe target for the treatment of VSMC growth-related cardiovascular disease. Deduced from these challenges the following two major hypotheses will be surveyed: (i) we hypothesize that Nox 4, a protein related to phagocytic NAD(P)H oxidase, is specifically recruited to the activated epidermal growth factor receptor (EGF-R). Reactive oxygen species (ROS) produced by Nox4 inactivate Shp2. Resveratrol is expected to specifically interfere with Nox4-dependent ROS production and thus to maintain higher levels of active Shp2. (ii) we hypothesize that Shp2 may be a suitable and safe target for the treatment of VSMC growth-related cardiovascular disease. For this purpose, the effect of resveratrol on other EGF-induced signalling pathways in VSMC as well as on tumour cells with aberrantly high EGF-R activity will be examined. The requirement of Shp2 for the observed effects will be investigated. From this study we expect to learn more about the interaction of important signalling molecules (Nox proteins, the protein tyrosine phosphatase Shp2, EGF-R) and their impact in cell growth-related disease. Further characterisation of the mode of resveratrol action is supposed to contribute to new strategies for the successful interference with signalling pathways involved in cardiovascular disease.

Cardiovascular disease is the leading cause of death in the western world. One major molecular player in the development of cardiovascular disease is angiotensin II (Ang II). It promotes growth and migration of vascular smooth muscle cells (VSMC), vascular oxidative stress and the production of growth factors and pro-inflammatory cytokines by VSMC. Ang II thereby contributes to the development of vascular damage associated with atherosclerosis, hypertension, vasculitis and diabetes. We have recently shown that resveratrol, a natural stilbene derivative, found in wines and thought to harbour major health benefits, inhibits Ang II-induced VSMC hypertrophy by interfering with the phosphatidylinositol-3-kinase (PI3 K)/Akt pathway. Seeking the molecular target of resveratrol we identified the protein tyrosine phosphatase (PTP) Shp2. Shp2 is activated by resveratrol and active Shp2 clears phospho-binding sites for the regulatory subunit p85 of PI 3 K on the adapter molecule Gab1, thus, interrupting further signalling to the PI 3 K/Akt pathway. The scientific challenges emerging from these data are (1) to clarify how resveratrol actvates the protein tyrosine phosphatase Shp2, and (2) to show whether Shp2 may be in general a suitable and safe target for the treatment of VSMC growth-related cardiovascular disease. Deduced from these challenges the following two major hypotheses will be surveyed: 1. We hypothesize that Nox 4, a protein related to phagocytic NAD(P)H oxidase, is specifically recruited to the activated epidermal growth factor receptor (EGF-R). Reactive oxygen species (ROS) produced by Nox4 inactivate Shp2. Resveratrol is expected to specifically interfere with Nox4-dependent ROS production and thus to maintain higher levels of active Shp2. 2. We hypothesize that Shp2 may be a suitable and safe target for the treatment of VSMC growth-related cardiovascular disease. For this purpose, the effect of resveratrol on other EGF-induced signalling pathways in VSMC as well as on tumour cells with aberrantly high EGF-R activity will be examined. The requirement of Shp2 for the observed effects will be investigated. From this study we expect to learn more about the interaction of important signalling molecules (Nox proteins, the protein tyrosine phosphatase Shp2, EGF-R) and their impact in cell growth-related disease. Further characterisation of the mode of resveratrol action is supposed to contribute to new strategies for the successful interference with signalling pathways involved in cardiovascular disease.