C-Peptide Induces Vascular Smooth Muscle Cell Proliferation: Involvement of Src-Kinase, Phosphatidylinositol 3-Kinase, and Extracellular Signal-Regulated Kinase 1/2

• Published in: Circulation research Vol. 99; no. 11; pp. 1181 - 1187
• Main Authors: Walcher, Daniel, Babiak, Christina, Poletek, Paulina, Rosenkranz, Stephan, Bach, Helga, Betz, Susanne, Durst, Renate, Grüb, Miriam, Hombach, Vinzenz, Strong, Jack, Marx, Nikolaus
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 24.11.2006; Lippincott
• Subjects: Animals; Arteriosclerosis - metabolism; Arteriosclerosis - pathology; Biological and medical sciences; C-Peptide - pharmacology; Cell Proliferation - drug effects; Cells, Cultured; Cyclin D1 - metabolism; Diabetes. Impaired glucose tolerance; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - pathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation - drug effects; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Humans; Intracellular Membranes - metabolism; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Phosphotransferases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats; Retinoblastoma Protein - metabolism; Signal Transduction; src-Family Kinases - metabolism; Vertebrates: cardiovascular system; Endocrinopathy; Cell proliferation; Extracellular signal-regulated protein kinase; proliferation; Enzyme; Transferases; Diabetes mellitus; Smooth muscle; C-Peptide; 1-Phosphatidylinositol 3-kinase; Restenosis; smooth muscle cells; Vertebrata; Mammalia; Kinase; Circulatory system
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/01.RES.0000251231.16993.88

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.