4-(5-benzo(1-3)dioxol-5-yl-4-pyridin-2-yl-1h-imidazol-2-yl)benzamide and Diabetes-Mellitus

Many cell and tissue abnormalities in diabetes mellitus are mediated by auto- and paracrine TGFbeta which is induced by high ambient glucose and glycated proteins. In most cell types TGFbeta reduces cell proliferation and enhances apoptosis which are mediated through the TGFbeta type I receptor, Alk5. In contrast, early diabetic microangiopathy is characterized by endothelial cell proliferation. Endothelial cells are unique in expressing a second TGFbeta type I receptor, Alk1, as well as the co-receptor, endoglin which increases the affinity of the ligand to Alk1. In differentiated blood outgrowth endothelial cells from normal subjects Alk1 and endoglin are constitutively expressed. Incubation with high glucose (HG) and glycated albumin (gAlb) induces Alk5 and raises TGFbeta secretion 3-fold without affecting Alk1 or endoglin levels. This diabetic milieu accelerates cell proliferation, at least in part, through TGFbeta/Alk1-smad1/5 and probably involving VEGF as well as pro-migratory MMP2 downstream of Alk1. In contrast, HG/gAlb also increases caspase-3 activity (suggesting increased apoptosis) in part but not entirely using a TGFbeta/Alk5-smad2/3 pathway. The findings support pleiotropy of TGFbeta in endothelial cells including proliferative effects (through Alk1-smad1/5) and pro-apoptotic signals (through Alk5-smad2/3).

Topics: Activin Receptors, Type II; Apoptosis; Benzamides; Biological Assay; Caspase 3; Cell Culture Techniques; Cell Differentiation; Cell Proliferation; Cells, Cultured; Coated Materials, Biocompatible; Collagen Type I; Culture Media, Conditioned; Culture Media, Serum-Free; Diabetes Mellitus; Dioxoles; Dose-Response Relationship, Drug; Endothelial Cells; Endothelium, Vascular; Enzyme Activation; Fibronectins; Genes, Reporter; Glucose; Humans; Luciferases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Recombinant Proteins; Smad Proteins; Time Factors; Transforming Growth Factor beta