George Vardatsikos

Insulino-mimetic and anti-diabetic effects of zinc.

While it has long been known that zinc (Zn) is crucial for the proper growth and maintenance of normal biological functions, Zn has also been shown to exert insulin-mimetic and anti-diabetic effects. These insulin-like properties have been demonstrated in isolated cells, tissues, and different animal models of type 1 and type 2 diabetes. Zn treatment has been found to improve carbohydrate and lipid metabolism in rodent models of diabetes. In isolated cells, it enhances glucose transport, glycogen and lipid synthesis, and inhibits gluconeogenesis and lipolysis. The molecular mechanism responsible for the insulin-like effects of Zn compounds involves the activation of several key components of the insulin signaling pathways, which include the extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3-K)/protein kinase B/Akt (PKB/Akt) pathways. However, the precise molecular mechanisms by which Zn triggers the activation of these pathways remain to be clarified. In this review, we provide a brief history of zinc, and an overview of its insulin-mimetic and anti-diabetic effects, as well as the potential mechanisms by which zinc exerts these effects.

Role of insulin-like growth factor 1 receptor and c-Src in endothelin-1- and angiotensin II-induced PKB phosphorylation, and hypertrophic and proliferative responses in vascular smooth muscle cells.

Endothelin-1 (ET-1) and angiotensin II (Ang II) are vasoactive peptides believed to contribute to the pathogenesis of vascular abnormalities such as hypertension, atherosclerosis, hypertrophy, and restenosis. The concept of transactivation of growth factor receptors, such as epidermal growth factor receptor (EGFR), in triggering vasoactive peptide-induced signaling events has gained much recognition during the past several years. We have demonstrated that insulin-like growth factor type 1 receptor (IGF-1R) plays a role in transducing the effect of H2O2, leading to protein kinase B (PKB) phosphorylation. Since vasoactive peptides elicit their responses through generation of reactive oxygen species, including H2O2, we investigated whether IGF-1R transactivation plays a similar role in ET-1- and Ang II-induced PKB phosphorylation and hypertrophic responses in vascular smooth muscle cells (VSMC). AG1024, a specific inhibitor of IGF-1R protein tyrosine kinase (PTK), attenuated both ET-1- and Ang II-induced PKB phosphorylation in a dose-dependent manner. ET-1 and Ang II treatment also induced the phosphorylation of tyrosine residues in the autophosphorylation sites of IGF-1R, which were blocked by AG1024. In addition, both ET-1 and Ang II evoked tyrosine phosphorylation of c-Src, a nonreceptor PTK, whereas pharmacological inhibition of c-Src PTK activity by PP2, a specific inhibitor of Src-family tyrosine kinase, significantly reduced PKB phosphorylation as well as tyrosine phosphorylation of IGF-1R induced by the 2 vasoactive peptides. Furthermore, protein and DNA synthesis enhanced by ET-1 and Ang II were attenuated by AG1024 and PP2. In conclusion, these data suggest that IGF-1R PTK and c-Src PTK play a critical role in mediating PKB phosphorylation as well as hypertrophic and proliferative responses induced by ET-1 and Ang II in A10 VSMC.

Involvement of Growth Factor Receptor and Nonreceptor Protein Tyrosine Kinases in Endothelin-1 and Angiotensin II-Induced Signaling Pathways in the Cardiovascular System

Endothelin-1 (ET-1) and angiotensin II (Ang II) play important roles in maintaining blood pressure and vascular homeostasis, and a heightened activity of these vasoactive peptides are thought to contribute to the development of vascular pathologies, such as hypertension, atherosclerosis, hypertrophy, and restenosis. This is caused by an excessive activation of several growth and proliferative signaling pathways, which include members of the mitogen-activated protein kinase (MAPK) family, as well as the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) pathway. ET-1 and Ang II stimulate these pathways through the activation of transmembrane guanine nucleotide-binding protein-coupled receptors (GPCRs). While the activation of these signaling pathways is well elucidated, the upstream elements responsible for ET-1 and Ang II-induced MAPK and PI3-K/PKB activation remain poorly understood. During the last several years, the concept of transactivation of receptor protein tyrosine kinases (PTKs), such as EGFR, IGF-1R, and nonreceptor PTK, in triggering vasoactive peptide-induced signaling events has gained much recognition. As such, in this chapter, we provide an overview of the role of receptor and nonreceptor PTKs in modulating ET-1 and Ang II-induced PI3-K/PKB and MAPK signaling events in vascular smooth muscle cells (VSMC), and their potential implication in vascular pathology.