title: C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2.
abstract: Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (VSMCs) proliferation and evaluated intracellular signaling pathways involved. In early arteriosclerotic lesions of diabetic subjects, C-peptide colocalized with VSMCs in the media. In vitro, stimulation of human or rat VSMCs with C-peptide induced cell proliferation in a concentration-dependent manner with a maximal 2.6+/-0.8-fold induction at 10 nmol/L human C-peptide (P<0.05 compared with unstimulated cells; n=9) and a 1.8+/-0.2-fold induction at 0.5 nmol/L rat C-peptide (P<0.05 compared with unstimulated cells; n=7), respectively, as shown by [H3]-thymidin incorporation. The proliferative effect of C-peptide on VSMCs was inhibited by Src short interference RNA transfection, PP2, an inhibitor of Src-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide-induced VSMC proliferation. Finally, C-peptide induced cyclin D1 expression as well as phosphorylation of Rb in VSMCs. Our results demonstrate that C-peptide induces VSMC proliferation through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus.
authors.affiliation: Department of Internal Medicine II, Cardiology, University of Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Walcher
authors.forename: Christina
authors.initials: C
authors.lastname: Babiak
authors.forename: Paulina
authors.initials: P
authors.lastname: Poletek
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.forename: Helga
authors.initials: H
authors.lastname: Bach
authors.forename: Susanne
authors.initials: S
authors.lastname: Betz
authors.forename: Renate
authors.initials: R
authors.lastname: Durst
authors.forename: Miriam
authors.initials: M
authors.lastname: Grüb
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Hombach
authors.forename: Jack
authors.initials: J
authors.lastname: Strong
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Marx
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D002096:C-Peptide / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002096:C-Peptide; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3